Technology for Modulating Targeting Chimeras Induced by Cell-Penetrating Peptide and Application Thereof

ABSTRACT

The invention provides a modulating targeting chimera molecule induced by a cell-penetrating peptide comprising at least one cell-penetrating peptide module, at least one targeting peptide module and at least one small molecule ligand module connected with each other, wherein the targeting peptide module is a peptide sequence that can bind to a targeted protein. The characteristics and advantages of the invention are as follows: in the modulating targeting chimera molecule induced by the cell-penetrating peptide provided by the invention, a modulating design is adopted, each sequence or small molecule compound module with different functions can be replaced and superimposed as required, and cyclization or secondary microprotein structural modification can be performed on all peptide modules. Under this design idea, the application effect and scope of targeted drugs are greatly enhanced.

CROSS REFERENCE TO RELATED APPLICATION(S)

This application claims the benefit of U.S. Provisional Patent Application No. 63/217,115, filed on Jun. 30, 2021, incorporated herein by reference as if fully set forth herein.

REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

The contents of the electronic sequence listing (DOP2121000006US Sequence Listing_S25.txt; Size: 228,742 bytes; and Date of Creation: Apr. 28, 2023) is incorporated herein by reference in its entirety.

FIELD

The invention relates to the field of bioengineering, in particular to the technology for a modulating targeted chimera induced by a cell-penetrating peptide and application thereof.

BACKGROUND

Technology for protein degraders has become popular in the world in recent years. The earliest and most popular technology is the technology of Proteolysis targeting Chimera (PROTAC). Structurally, PROTAC comprises three components: a small molecule E3 ubiquitin ligase ligand and a small molecule target protein ligand, as well as a specially designed “Linker” structure through which the two active ligands are connected and finally the active form of “PROTAC” of the small molecule triplet is formed with a structure as follows: a small molecule ligand (for targeting a target protein)+linker+small molecule ligand (for binding to E3 ligase). The target protein binds to the small molecule target protein ligand, and the E3 ligase ligand also binds to its ligand. A ubiquitin label is added to the target protein by the E3 ligase, and then after multiple rounds of ubiquitination, there are multiple ubiquitin labels. The target protein after polyubiquitination will be recognized and degraded by the proteasome.

The PROTAC technology has been successfully applied to the induced degradation of a variety of pathological proteins. In nature, a special recognition signal is required for E3 ubiquitin ligase to recruit and ubiquitinate its target protein. The appearance of the PROTAC technology enables E3 to ubiquitinate any protein. In this technology, a dual-function molecule is designed, with one end of which can bind to a target protein while the other end binds to E3 ligase, combining the two into a polymer. E3 then ubiquitinates the target protein and guides it into the degradation pathway. The most attractive aspect of the targeted protein degradation is that it can target those protein targets that are traditionally considered non-pharmaceutical, which may account for more than 80% of the human proteome. Since the targeted protein degradation strategy can selectively degrade proteins by binding to almost any site on the protein rather than the active site, theoretically this strategy can be used for any protein.

However, in actual research or operation, it is very difficult to screen out the small molecule ligand component of the above small molecule “triplet” PROTAC that binds to the target protein. Due to the inability to find suitable ligands for many targets, targeted drugs of which cannot be developed. Moreover, in nature, many protein targets are naturally not suitable for small molecule binding, which may lead to the failure of drug research and development of small molecule PROTAC.

Existing therapeutic drugs are mainly concentrated in two categories: small molecules and biologics. However, due to the limitations of their own biophysical properties, these two types of therapeutic drugs cannot effectively cover all these confirmed important molecular targets. Peptide drugs are another class of targeted molecules that have attracted widespread attention and interest. Similar to biological macromolecules, peptide molecules also have high binding ability and selectivity for targets, and have less off-target effects than small molecule drugs. The metabolites of peptides in the body are amino acids, which minimizes toxicity. Compared with small molecule drugs, peptide drugs have incomparable advantages, which are mainly reflected in the ease of modification, the specificity of target recognition, and the wide targeting range of peptide molecules.

SUMMARY

An object of the present invention is to provide a technology for modulating targeting chimeras induced by a cell-penetrating peptide that can target a target protein thereby effectively degrading the target protein, and applications thereof, that is, a technology for Cell-penetrating-peptide Induced Targeting Chimera (CePPiTAC) for use in degrading the target protein.

The object of the present invention described above can be realized by using the following technical solutions:

The first object of the present invention is to provide a modulating targeting chimera molecule induced by a cell-penetrating peptide, comprising at least one cell-penetrating peptide module, at least one targeting peptide module, one (or no) small molecule Linker module and at least one small molecule ligand module connected with each other, wherein the targeting peptide module is a peptide sequence that can bind to a targeted protein.

Optionally, the modulating targeting chimera molecule induced by the cell-penetrating peptide described above further comprises at least one Linker module, wherein the targeting peptide module is chimeric with the small molecule ligand module through the Linker module.

Optionally, the modulating targeting chimera molecule induced by the cell-penetrating peptide described above, wherein the cell-penetrating peptide module is connected to the free end of the targeting peptide module and used to guide the targeting chimera molecule for penetrating the cell membrane.

Optionally, the modulating targeting chimera molecule induced by the cell-penetrating peptide described above, wherein the small molecule ligand module is a small molecule E3 ligand that can bind to E3 ligase, preferably, the protease degrader adapted to the small molecule E3 ligand is one or more of CRBN (Cereblon protein), VHL (von Hippel-Lindau) and IAP (Inhibitor of apoptosis proteins).

Optionally, the modulating targeting chimera molecule induced by the cell-penetrating peptide described above, wherein the cell-penetrating peptide module has an amino acid sequence of any one of SEQ ID NO: 1-SEQ ID NO: 3.

Optionally, the modulating targeting chimera molecule induced by the cell-penetrating peptide described above, wherein the targeting peptide module has an amino acid sequence of any one or more of SEQ ID NO: 4-SEQ ID NO: 17.

Optionally, the modulating targeting chimera molecule induced by the cell-penetrating peptide described above, wherein the Linker module is a small molecule compound with a structural formula shown in formula I:

Optionally, the modulating targeting chimera molecule induced by the cell-penetrating peptide described above, wherein:

when the adapted protease degrader is CRBN, the structural formula of the small molecule ligand module is shown in formula II:

when the adapted protease degrader is VHL, the structural formula of the small molecule ligand module is shown in formula III:

and

when the adapted protease degrader is TAP, the structural formula of the small molecule ligand module is as shown in formula IV:

Optionally, the modulating targeting chimera molecule induced by the cell-penetrating peptide described above has a structure of any one or more of the following structures:

1) the cell-penetrating peptide of SEQ ID NO: 1+the targeting peptide of SEQ ID NO: 4+the Linker of formula I+the small molecule ligand of formula II;

2) the cell-penetrating peptide of SEQ ID NO: 2+the targeting peptide of SEQ ID NO: 5+the Linker of formula I+the small molecule ligand of formula III;

3) the cell-penetrating peptide of SEQ ID NO: 1+the targeting peptide of SEQ ID NO: 5+the Linker of formula I+the small molecule ligand of formula IV;

4) the cell-penetrating peptide of SEQ ID NO: 1+the targeting peptide of SEQ ID NO: 6+the Linker of formula I+the small molecule ligand of formula II;

5) the cell-penetrating peptide of SEQ ID NO: 1+the targeting peptide of SEQ ID NO: 7+the Linker of formula I+the small molecule ligand of formula III;

6) the cell-penetrating peptide of SEQ ID NO: 1+the targeting peptide of SEQ ID NO: 8+the Linker of formula I+the small molecule ligand of formula II;

7) the cell-penetrating peptide of SEQ ID NO: 1+the targeting peptide of SEQ ID NO: 9+the Linker of formula I+the small molecule ligand of formula III;

8) the cell-penetrating peptide of SEQ ID NO: 1+the targeting peptide of SEQ ID NO: 10+the Linker of formula I+the small molecule ligand of formula II;

9) the cell-penetrating peptide of SEQ ID NO: 1+the targeting peptide of SEQ ID NO: 11+the Linker of formula I+the small molecule ligand of formula IV;

10) the cell-penetrating peptide of SEQ ID NO: 1+the targeting peptide of SEQ ID NO: 12+the Linker of formula I+the small molecule ligand of formula III;

11) the cell-penetrating peptide of SEQ ID NO: 1+the targeting peptide of SEQ ID NO: 13+the Linker of formula I+the small molecule ligand of formula III;

12) the cell-penetrating peptide of SEQ ID NO: 3+the targeting peptide of SEQ ID NO: 14+the Linker of formula I+the small molecule ligand of formula IV;

13) the cell-penetrating peptide of SEQ ID NO: 1+the targeting peptide of SEQ ID NO: 15+the Linker of formula I+the small molecule ligand of formula II;

14) the cell-penetrating peptide of SEQ ID NO: 1+the targeting peptide of SEQ ID NO: 16+the Linker of formula I+the small molecule ligand of formula II;

15) the cell-penetrating peptide of SEQ ID NO: 2+the targeting peptide of SEQ ID NO: 17+the Linker of formula I+the small molecule ligand of formula IV;

16) the cell-penetrating peptide of SEQ ID NO: 3+the targeting peptide of SEQ ID NO: 14+the Linker of formula I+(dual E3 ligands: the small molecule ligand of formula II+the small molecule ligand of formula III); and

17) the cell-penetrating peptide of SEQ ID NO: 1+(dual targets: the targeting peptide of SEQ ID NO: 4+the targeting peptide of SEQ ID NO: 5)+the Linker of formula I+the small molecule ligand of formula II.

Optionally, the modulating targeting chimera molecule induced by the cell-penetrating peptide described above, wherein the targeting peptide module further comprises a modified stapled peptide sequence or circular peptide sequence, and the stapled peptide sequence or circular peptide sequence has a function of cell penetration. In this case, the modulating targeting chimera molecule induced by the cell-penetrating peptide can be achieved without the cell-penetrating peptide.

Optionally, the modulating targeting chimera molecule induced by the cell-penetrating peptide described above, wherein the stapled peptide has a structural formula shown in formula V:

and

the cyclic peptide has a structural formula shown in formula VI:

Optionally, the modulating targeting chimera molecule induced by the cell-penetrating peptide described above, wherein the modulating targeting chimera molecule induced by the cell-penetrating peptide containing the stapled peptide has the structure as follows: the stapled peptide of formula V+the Linker of formula I+the small molecule ligand of formula II.

Optionally, the modulating targeting chimera molecule induced by the cell-penetrating peptide described above, wherein the modulating targeting chimera molecule induced by the cell-penetrating peptide containing the circular peptide has the structure as follows: the circular peptide of formula VI+the Linker of formula I+the small molecule ligand of formula II.

The second object of the present invention is to provide a use of the modulating targeting chimera molecule induced by the cell-penetrating peptide described above in preparing a product for degrading a targeted protein or a product for degrading a targeted protein with a mutant amino acid position.

Optionally, the use described above, wherein the degraded targeted protein comprises one or more of the novel coronavirus S protein HR2, novel coronavirus N protein, novel coronavirus M protein, novel coronavirus E protein, novel coronavirus Orf6 protein, LAG-3 protein, Her2 protein, SHP-2 protein, STAT5B protein, MUC16 protein, CTLA-4 protein, PCSK9 protein, PD-1 protein, PD-L1 protein and KRAS protein with G12V mutation.

Based on the above technical description, the core idea of the present invention is to connect multiple freely transformable “module” sequences or small molecular compounds to form “modulating” targeting chimera molecules with strong targeting ability, good cell-penetration effect and high degradation efficiency.

In the technical solution of the present invention, the most basic composition is a cell-penetrating peptide module, a targeting peptide module and a small molecule ligand module, which are connected to each other. The further composition can be a cell-penetrating peptide module, a targeting peptide module, a Linker module and a small molecule ligand module, thereby forming the basic structure of the cell-penetrating peptide-targeting peptide-Linker-small molecule ligand.

The basic structure of the cell-penetrating peptide-targeting peptide-small molecule ligand can direct the small molecule ligand to the target protein. Although some chimeras under this basic structure can exert targeted therapeutic properties, they have certain defects. For example, the connection of the three is not stable and easy to fall off.

The cell-penetrating peptide-targeting peptide-Linker-small molecule ligand is an upgraded structure of the above basic structure, which overcomes the defects of poor cell penetration performance of targeting peptides and unstable direct connection between targeting peptides and small molecule ligands. Through penetrating the membrane by the cell-penetrating peptide, the targeting peptide can be directed to the target protein, so as to achieve the effect of targeted penetration. Using the Linker to connect the two can effectively reduce the probability of falling off; meanwhile, it overcomes defects of both poor cell penetration and unstable connection, solving the technical effect of targeted therapy almost perfectly and improving the targeting efficiency. The most important technical point is that, by using the cell-penetrating peptide+targeting peptide in this optimal structure for “replacing” the targeting proteins in the existing PROTAC technology, the selectivity of targeted peptides to targeted proteins can be greatly expanded, and almost all known target proteins can be targeted and degraded through a linked small molecule ligand (E3).

Penetration into cells through cell membranes is a prerequisite for the functioning of many biological macromolecules whose targets are in the cell. However, the biological barrier function of the biofilm prevents many macromolecules from entering the cell, thus limiting the application of these substances in the field of therapy to a great extent. Therefore, how to guide these substances to penetrate the cell membrane is an urgent problem to be solved. As an intermediate product of protein hydrolysis, peptide has poor ability for cell penetration. In recent years, with the development of technology, it has gradually been discovered that the transactivator (TAT) in human immunodeficiency virus (HIV) can effectively pass through the cell membrane and enter the cell, followed by a variety of proteins capable of penetrating cell membranes were discovered and named as cell-penetrating peptides (CPPs). In general, cell-penetrating peptides are usually peptide molecules of no more than 30 amino acids that can independently pass through the cell membrane independent of specific membrane receptors. Used as a tool for intracellular transport of bioactive molecules, these cell-penetrating peptides have characteristics of low toxicity, convenience and effectiveness compared with other iontophoresis and nano carriers, and play a more and more important role in drug development. Even some drugs containing CPPs have passed FDA's clinical trials.

In the Cell-penetrating-peptide Induced Targeting Chimera (CePPiTAC) technology of the present invention, the peptide that can bind to the target protein “replaces” the component of the small molecule target protein ligand in the common “triplet” PROTAC structure, by which the Linker and the small molecule E3 ligand are connected, and a sequence of a cell-penetrating peptide is added to form a structure as: the cell-penetrating peptide (cell-penetrating peptide)+peptide (targeting the target)+Linker+E3 ligand. The Linker can be removed if necessary, allowing the peptide containing the cell-penetrating peptide (targeting the target) to be directly linked to the E3 ligand.

The drug synthesized by the present invention is a complex of peptides and small molecules, a small molecule Linker can be connected therebetween or be removed. At the non-small molecular junction of the peptide, a cell-penetrating peptide sequence can be added, which can carry the peptide-small molecule complex (CePPiTAC complex) into the cell. Meanwhile, the component of the peptide targeting a target protein can bind to the target protein, while the small molecule E3 ligand at the other end of the Linker can bind to E3 ligase and initiate E3 ubiquitinase reaction to ubiquitinate the target protein, so that the 26S protease in the cell can recognize the target protein for degradation.

The features and advantages of the present invention are as follows: the modulating targeting chimera molecule induced by the cell-penetrating peptide provided by the present invention can penetrate the cell membrane and target all targeted proteins through interconnected cell-penetrating peptides, targeting peptides and small molecule ligands, in which the connected small molecule ligands can bind to the immobilized ligase and initiate a ubiquitinase reaction, thereby ubiquitinating the target protein, so that intracellular proteases can target and recognize the target protein for degradation, thus the targeted drugs can be screened out more extensively. Since the peptide module is used to bind the target protein, in theory, all target proteins can be targeted, which cannot be achieved by other degrader technologies in the past. In addition, since in this technology, ubiquitination is achieved by combining high-efficiency small molecule E3 ligands, it is much more efficient than other peptide-based PROTAC/degraders that use peptide ligands. In most cases, degradation of target proteins can be achieved at the nmol level in cell experiments.

In this chimera molecule structure, a Linker can also be added, and the addition of the Linker can further solidify the connection between the targeting peptide and the small molecule ligand.

Meanwhile, in the targeting chimera molecule provided by the present invention, a modulating design is adopted, and each sequence or small molecule compound module with different functions can be replaced and superimposed as needed. Under this design idea, the application effect and scope of targeted drugs are greatly enhanced.

Targets that can be developed for the small molecule triplet PROTAC are Limited, while Peptide-Based PROTAC/degrader has low degradation efficiency, and the target can only be degraded on the cell at the umol level. However, under this technology, all the targets can be targeted, while high-efficiency degradation (cellular degradation) can also be achieved at the nmol level, truly achieving the purpose of “drugs for all diseases”. Meanwhile, the present invention also has subversive significance to the previous technical concepts. Taking virus-related proteins as an example, the relevant targets for viruses were mainly related proteins that infect human cells (such as the S protein of novel coronavirus), as well as enzymes needed for virus synthesis, but there were few targets to choose. However, in this technology, the peptide sequence is used to bind to the inactive site of the target, which can target all proteins of all viruses for degradation, and is also effective in overcoming drug resistance caused by virus mutation, which greatly improves the possibility and convenience of successful research and development of drugs for virus. In addition, under this technology, a single mutation of a certain target can be degraded, while the wild-type homologous protein without such a mutation will not be affected or be less affected, which cannot be realized for other degrader technologies such as PROTAC.

BRIEF DESCRIPTION OF DRAWINGS

In order to illustrate the technical solutions in the embodiments of the present invention more clearly, the following briefly introduces the accompanying drawings used in the description of the embodiments. Obviously, the accompanying drawings in the following description are only some embodiments of the present invention. For those of ordinary skill in the art, other drawings can also be obtained from these drawings without creative effort.

FIG. 1 shows a conventional design of the modulating targeting chimera molecule induced by the cell-penetrating peptide (targeting degrader) described in Example 2 of the present invention, i.e., a universal pattern of the cell-penetrating peptide-targeting peptide-Linker-small molecule ligand.

FIG. 2 shows the modulating targeting chimera molecule induced by the cell-penetrating peptide described in Example 3 of the present invention, which is specially designed for one or a certain class of refractory pathogenic proteins, and can combine the targeting peptide with two or multiple different E3 ligase conjugates to efficiently degrade target pathogenic proteins.

FIG. 3 shows the modulating targeting chimera molecule induced by the cell-penetrating peptide described in Example 4 of the present invention, which can effectively target multiple targets related to the formation of protein-protein complexes of pathogenic proteins, thereby achieving the efficacy of targeting pathogenic proteins and effectively inhibiting the entire pathogenic pathway as well as completely inhibiting a specific disease by degrading multiple targets.

FIG. 4 shows a process flow chart of the solid-phase synthesis of the peptide in Example 5, wherein the synthetic product peptide is marked as 1.

FIG. 5 shows the synthesis reaction of the synthetic compound of lenalidomide and succinic anhydride in Example 5, wherein lenalidomide is marked as 2, succinic anhydride as 3, and the synthetic product as 4.

FIG. 6 shows a process flow chart of the solid-phase synthesis of the LEN-binding peptide in Example 5, wherein the synthesis product (mixture of diastereomers) is marked as 5.

FIG. 7A-FIG. 7C show the modulating targeting chimera molecule induced by the cell-penetrating peptide for degrading novel coronavirus S protein HR2 in an example of the present invention and the effect verification thereof, in which FIG. 7A is a structural diagram of the modulating targeting chimera molecule induced by the cell-penetrating peptide, FIG. 7B is the verification of the degradation effect on the protein, and FIG. 7C shows the verification by a protease inhibitor MG132 that the effect is indeed produced by the protease degrader.

FIG. 8A-FIG. 8C show the modulating targeting chimera molecule induced by the cell-penetrating peptide for degrading novel coronavirus N protein in an example of the present invention and the effect verification thereof, in which FIG. 8A is a structural diagram of the modulating targeting chimera molecule induced by the cell-penetrating peptide, FIG. 8B is the verification of the degradation effect on the protein, and FIG. 8C shows the verification by a protease inhibitor MG132 that the effect is indeed produced by the protease degrader.

FIG. 9A-FIG. 9C show the modulating targeting chimera molecule induced by the cell-penetrating peptide for degrading novel coronavirus M protein in an example of the present invention and the effect verification thereof, in which FIG. 9A is a structural diagram of the modulating targeting chimera molecule induced by the cell-penetrating peptide, FIG. 9B is the verification of the degradation effect on the protein, and FIG. 9C shows the verification by a protease inhibitor MG132 that the effect is indeed produced by the protease degrader.

FIG. 10A-FIG. 10C show the modulating targeting chimera molecule induced by the cell-penetrating peptide for degrading novel coronavirus E protein in an example of the present invention and the effect verification thereof, in which FIG. 10A is a structural diagram of the modulating targeting chimera molecule induced by the cell-penetrating peptide, FIG. 10B is the verification of the degradation effect on the protein, and FIG. 10C shows the verification by a protease inhibitor MG132 that the effect is indeed produced by the protease degrader.

FIG. 11A-FIG. 11C show the modulating targeting chimera molecule induced by the cell-penetrating peptide for degrading novel coronavirus Orf6 protein in an example of the present invention and the effect verification thereof, in which FIG. 11A is a structural diagram of the modulating targeting chimera molecule induced by the cell-penetrating peptide, FIG. 11B is the verification of the degradation effect on the protein, and FIG. 11C shows the verification by a protease inhibitor MG132 that the effect is indeed produced by the protease degrader.

FIG. 12A-FIG. 12C show the modulating targeting chimera molecule induced by the cell-penetrating peptide for degrading Lag-3 protein in an example of the present invention and the effect verification thereof, in which FIG. 12A is a structural diagram of the modulating targeting chimera molecule induced by the cell-penetrating peptide, FIG. 12B is the verification of the degradation effect on the protein, and FIG. 12C shows the verification by a protease inhibitor MG132 that the effect is indeed produced by the protease degrader.

FIG. 13A-FIG. 13C show the modulating targeting chimera molecule induced by the cell-penetrating peptide for degrading Her2 protein in an example of the present invention and the effect verification thereof, in which FIG. 13A is a structural diagram of the modulating targeting chimera molecule induced by the cell-penetrating peptide, FIG. 13B is the verification of the degradation effect on the protein, and FIG. 13C shows the verification by a protease inhibitor MG132 that the effect is indeed produced by the protease degrader.

FIG. 14A-FIG. 14C show the modulating targeting chimera molecule induced by the cell-penetrating peptide for degrading SHP-2 protein in an example of the present invention and the effect verification thereof, in which FIG. 14A is a structural diagram of the modulating targeting chimera molecule induced by the cell-penetrating peptide, FIG. 14B is the verification of the degradation effect on the protein, and FIG. 14C shows the verification by a protease inhibitor MG132 that the effect is indeed produced by the protease degrader.

FIG. 15A-FIG. 15C show the modulating targeting chimera molecule induced by the cell-penetrating peptide for degrading STAT5B protein in an example of the present invention and the effect verification thereof, in which FIG. 15A is a structural diagram of the modulating targeting chimera molecule induced by the cell-penetrating peptide, FIG. 15B is the verification of the degradation effect on the protein, and FIG. 15C shows the verification by a protease inhibitor MG132 that the effect is indeed produced by the protease degrader.

FIG. 16A-FIG. 16C show the modulating targeting chimera molecule induced by the cell-penetrating peptide for degrading MUC16 protein in an example of the present invention and the effect verification thereof, in which FIG. 16A is a structural diagram of the modulating targeting chimera molecule induced by the cell-penetrating peptide, FIG. 16B is the verification of the degradation effect on the protein, and FIG. 16C shows the verification by a protease inhibitor MG132 that the effect is indeed produced by the protease degrader.

FIG. 17A-FIG. 17B show the modulating targeting chimera molecule induced by the cell-penetrating peptide for degrading CTLA-4 protein in an example of the present invention and the effect verification thereof, in which FIG. 17A is a structural diagram of the modulating targeting chimera molecule induced by the cell-penetrating peptide, and FIG. 17B is the verification of the degradation effect on the protein shows the verification.

FIG. 18A-FIG. 18B show the modulating targeting chimera molecule induced by the cell-penetrating peptide for degrading PCSK9 protein in an example of the present invention and the effect verification thereof, in which FIG. 18A is a structural diagram of the modulating targeting chimera molecule induced by the cell-penetrating peptide, and FIG. 18B shows the verification by a protease inhibitor MG132 that the effect is indeed produced by the protease degrader.

FIG. 19A-FIG. 19B show the modulating targeting chimera molecule induced by the cell-penetrating peptide for degrading PD-1 protein in an example of the present invention and the effect verification thereof, in which FIG. 19A is a structural diagram of the modulating targeting chimera molecule induced by the cell-penetrating peptide, and FIG. 19B shows the verification by a protease inhibitor MG132 that the effect is indeed produced by the protease degrader.

FIG. 20A-FIG. 20B show the modulating targeting chimera molecule induced by the cell-penetrating peptide for degrading PD-L1 protein in an example of the present invention and the effect verification thereof, in which FIG. 20A is a structural diagram of the modulating targeting chimera molecule induced by the cell-penetrating peptide, and FIG. 20B shows the verification by a protease inhibitor MG132 that the effect is indeed produced by the protease degrader.

FIG. 21A-FIG. 21C show the modulating targeting chimera molecule induced by the cell-penetrating peptide for precisely targeting and degrading KRAS protein with G12V mutation in an example of the present invention and the effect verification thereof, in which FIG. 21A is the structure diagram of the modulating targeting chimera molecule induced by the cell-penetrating peptide, FIG. 21B is the verification of the degradation effect on KRAS protein with G12V mutation, and FIG. 21C is the verification of the degradation effect on the non-mutated KRAS protein (wild type).

FIG. 22A-FIG. 22B show the modulating dual-E3 ligand targeting chimera molecule induced by the cell-penetrating peptide for degrading PCSK9 protein in an example of the present invention and the effect verification thereof, in which FIG. 22A is the structure diagram of the modulating dual-E3 ligand (CRBN+VHL) targeting chimera molecule induced by the cell-penetrating peptide FIG. 22B shows the verification by a protease inhibitor MG132 that the effect is indeed produced by the protease degrader and the overall dosage of the drug is less.

FIG. 23A-FIG. 23B show the modulating dual-target targeting chimera molecule induced by the cell-penetrating peptide for simultaneously degrading HR2 protein and N protein in an example of the present invention and the effect verification thereof, in which FIG. 23A is the structure diagram of the modulating dual target (targets of the novel coronavirus HR2+the novel coronavirus N protein) targeting chimera molecule induced by the cell-penetrating peptide, and FIG. 23B shows the verification by a protease inhibitor MG132 that the effect is indeed produced by the protease degrader.

FIG. 24A-FIG. 24B show the modulating stapled peptide-modified targeting chimera molecule induced by the cell-penetrating peptide for degrading PD-L1 protein in an example of the present invention and the effect verification thereof, in which FIG. 24A is the structure diagram of the modulating stapled peptide-modified targeting chimera molecule induced by the cell-penetrating peptide, and FIG. 24B is the verification of the degradation effect on the protein.

FIG. 25A-FIG. 25B show the modulating cyclic peptide-modified targeting chimera molecule induced by the cell-penetrating peptide for degrading PD-L1 protein in an example of the present invention and the effect verification thereof, in which FIG. 25A is the structure diagram of the modulating cyclic peptide-modified targeting chimera molecule induced by the cell-penetrating peptide, and FIG. 25B is the verification of the degradation effect on the protein.

FIG. 26A-FIG. 26C show a graph showing the validation of the staining of cell penetration of the modulating targeting chimera molecule induced by the cell-penetrating peptide in FIGS. 12A-14C.

FIG. 27A-FIG. 27B show a graph showing the validation of the staining of cell penetration of the modulating targeting chimera molecule induced by the cell-penetrating peptide in FIGS. 15A-C and FIGS. 16A-C.

FIG. 28A-FIG. 28B show a graph showing the validation of the staining of cell penetration of the modulating targeting chimera molecule induced by the cell-penetrating peptide in FIGS. 17A-C and FIGS. 18A-C.

FIG. 29A-FIG. 29B show a graph showing the validation of the staining of cell penetration of the modulating targeting chimera molecule induced by the cell-penetrating peptide in FIGS. 19A-C and FIGS. 20A-C.

FIGS. 30-32 show a structural representation of a stapled peptide+small molecule ligand chimera. Among them, terminal A of FIG. 30 is connected to terminal A of FIG. 31 , and terminal B of FIG. 31 is connected to terminal B of FIG. 32 . The combination of FIGS. 30-32 shows the structure of a chimera molecule compound containing a stapled peptide.

FIGS. 33-35 show another structural representation of a cyclic peptide+small molecule ligand chimera. Among them, terminal A of FIG. 33 is connected to terminal A of FIG. 34 , terminal B of FIG. 33 is connected to terminal B of FIG. 34 , and terminal D of FIG. 34 is connected to terminal D of FIG. 35 . The combination of FIGS. 33-35 shows the structure of a chimera molecule compound containing a cyclic peptide.

DETAILED DESCRIPTION

The technical solutions in the examples of the present invention will be clearly and completely described below with reference to the accompanying drawings in the examples of the present invention. Obviously, the described examples are only a part of the examples of the present invention, but not all of the examples. Based on the examples of the present invention, all other examples obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

Example 1

A modulating targeting chimera molecule induced by a cell-penetrating peptide comprises at least one cell-penetrating peptide module, at least one targeting peptide module and at least one small molecule ligand module connected with each other, wherein the targeting peptide module is a peptide sequence that can bind to a targeted protein.

The chimera molecule formed by the cell-penetrating peptide+targeting peptide+small molecule ligand can effectively target the small molecule ligand to the pathogenic target protein through the targeting peptide, so as to achieve the pertinence and specificity of drug treatment. In the field of treatment of various diseases (especially tumor diseases), it can exert more stable and broader effects.

There is one cell-penetrating peptide module, one, two, three or even more targeting peptide modules, and one, two, three or even more small molecule ligand modules.

The modulating targeting chimera molecule induced by the cell-penetrating peptide further comprises at least one Linker module for chimerizing the targeting peptide module and small molecule ligand module. Linker modules can be one, two, three or even more.

The cell-penetrating peptide module is connected to the free end of the targeting peptide module and used to guide the targeting chimera molecule for penetrating the cell membrane.

The small molecule ligand module is a small molecule E3 ligand that can bind to E3 ligase.

Preferably, the protease degrader adapted to the small molecule E3 ligand is one or more of CRBN, VHL, and IAP.

The cell-penetrating peptide module has an amino acid sequence of any one of SEQ ID NO: 1-SEQ ID NO: 3:

(SEQ ID NO: 1) YGRKKRRQRRR; (SEQ ID NO: 2) RRRRRRRR; and (SEQ ID NO: 3) RQIKIWFQNRRMKWK.

The targeting peptide module has an amino acid sequence of any one or more of SEQ ID NO: 4-SEQ ID NO: 17:

(SEQ ID NO: 4) SAIGKIQDSLSSTAS; (SEQ ID NO: 5) PQEESEEEVEEP; (SEQ ID NO: 6) GGKGLGKacGGA; (SEQ ID NO: 7) DTMVGWDKDARTK; (SEQ ID NO: 8) FNGARSFIDI; (SEQ ID NO: 9) WARLWNYLYR; (SEQ ID NO: 10) RSFIDIGSGT; (SEQ ID NO: 11) KAVDG(p)YVKPQI; (SEQ ID NO: 12) WIDPVNGDTE; (SEQ ID NO: 13) ARHPSWYRPFEGCG; (SEQ ID NO: 14) MESFPGWNLV(homoR)IGLLR; (SEQ ID NO: 15) FNWDYSLEELREKAKYK; (SEQ ID NO: 16) MPIFLDHILNKFWILHYA; and (SEQ ID NO: 17) LYDVAGSDKY.

The Linker module is a small molecule compound with a structural formula shown in formula I:

The modulating targeting chimera molecule induced by the cell-penetrating peptide, wherein:

when the adapted protease degrader is CRBN, the structural formula of the small molecule ligand module is shown in formula II:

when the adapted protease degrader is VHL, the structural formula of the small molecule ligand module is shown in formula III:

and

when the adapted protease degrader is TAP, the structural formula of the small molecule ligand module is as shown in formula IV:

The modulating targeting chimera molecule induced by the cell-penetrating peptide has a structure of any one or more of the following structures:

1) the cell-penetrating peptide of SEQ ID NO: 1+the targeting peptide of SEQ ID NO: 4+the Linker of formula I+the small molecule ligand of formula II;

2) the cell-penetrating peptide of SEQ ID NO: 2+the targeting peptide of SEQ ID NO: 5+the Linker of formula I+the small molecule ligand of formula III;

3) the cell-penetrating peptide of SEQ ID NO: 1+the targeting peptide of SEQ ID NO: 5+the Linker of formula I+the small molecule ligand of formula IV;

4) the cell-penetrating peptide of SEQ ID NO: 1+the targeting peptide of SEQ ID NO: 6+the Linker of formula I+the small molecule ligand of formula II;

5) the cell-penetrating peptide of SEQ ID NO: 1+the targeting peptide of SEQ ID NO: 7+the Linker of formula I+the small molecule ligand of formula III;

6) the cell-penetrating peptide of SEQ ID NO: 1+the targeting peptide of SEQ ID NO: 8+the Linker of formula I+the small molecule ligand of formula II;

7) the cell-penetrating peptide of SEQ ID NO: 1+the targeting peptide of SEQ ID NO: 9+the Linker of formula I+the small molecule ligand of formula III;

8) the cell-penetrating peptide of SEQ ID NO: 1+the targeting peptide of SEQ ID NO: 10+the Linker of formula I+the small molecule ligand of formula II;

9) the cell-penetrating peptide of SEQ ID NO: 1+the targeting peptide of SEQ ID NO: 11+the Linker of formula I+the small molecule ligand of formula IV;

10) the cell-penetrating peptide of SEQ ID NO: 1+the targeting peptide of SEQ ID NO: 12+the Linker of formula I+the small molecule ligand of formula III;

11) the cell-penetrating peptide of SEQ ID NO: 1+the targeting peptide of SEQ ID NO: 13+the Linker of formula I+the small molecule ligand of formula III;

12) the cell-penetrating peptide of SEQ ID NO: 3+the targeting peptide of SEQ ID NO: 14+the Linker of formula I+the small molecule ligand of formula IV;

13) the cell-penetrating peptide of SEQ ID NO: 1+the targeting peptide of SEQ ID NO: 15+the Linker of formula I+the small molecule ligand of formula II;

14) the cell-penetrating peptide of SEQ ID NO: 1+the targeting peptide of SEQ ID NO: 16+the Linker of formula I+the small molecule ligand of formula II;

15) the cell-penetrating peptide of SEQ ID NO: 2+the targeting peptide of SEQ ID NO: 17+the Linker of formula I+the small molecule ligand of formula IV;

16) the cell-penetrating peptide of SEQ ID NO: 3+the targeting peptide of SEQ ID NO: 14+the Linker of formula I+(dual E3 ligands: the small molecule ligand of formula II+the small molecule ligand of formula III); and

17) the cell-penetrating peptide of SEQ ID NO: 1+(dual targets: the targeting peptide of SEQ ID NO: 4+the targeting peptide of SEQ ID NO: 5)+the Linker of formula I+the small molecule ligand of formula II.

The targeting peptide module in the modulating targeting chimera molecule induced by the cell-penetrating peptide further comprises a modified stapled peptide sequence or circular peptide sequence.

The stapled peptide has the structural formula shown in formula V:

and

the cyclic peptide has the structural formula shown in formula VI:

The modulating targeting chimera molecule induced by the cell-penetrating peptide containing the stapled peptide has the structure as follows: the stapled peptide of formula V+the Linker of formula I+the small molecule ligand of formula II.

The modulating targeting chimera molecule induced by the cell-penetrating peptide containing the circular peptide has the structure as follows: the circular peptide of formula VI+the Linker of formula I+the small molecule ligand of formula II.

Example 2

The modulating targeting chimera molecule induced by the cell-penetrating peptide of Example 1 can be used in preparing a product for degrading a targeted protein or a product for degrading a targeted protein with a mutant amino acid position.

The degraded targeted protein comprises one or more of the novel coronavirus S protein HR2, novel coronavirus N protein, novel coronavirus M protein, novel coronavirus E protein, novel coronavirus Orf6 protein, LAG-3 protein, Her2 protein, SHP-2 protein, STAT5B protein, MUC16 protein, CTLA-4 protein, PCSK9 protein, PD-1 protein, PD-L1 protein and KRAS protein with G12V mutation.

Until now, targeting, inhibiting, and medicating proteins involved in protein-protein interactions has been nearly impossible with the help of inhibitor molecules. Targeting harmful/pathogenic proteins using proteosomal degradation mechanisms is a promising therapeutic approach. With the help of the ubiquitin-proteasome system (UPS), the target protein-protein interaction (PPI) interacts with the target protein via key peptide sequences to selectively degrade the “non-pharmaceutical” target protein. The inventors have devised a method for this bifunctional peptide-based degrader, which targets and degrades target proteins involved in PPIs. The inventors achieved the degradation of the expected target protein with the help of the Linker by binding the peptide with high affinity and selective interaction with the target protein to the E3 ligase. In order to achieve cell permeability of peptide degraders, the inventors further combined peptide degrader sequences with cell permeable peptides (cell-penetrating peptides). The design of the targeting degrader in general is shown in FIG. 1 below.

The inventors have found that peptide degraders were designed to degrade >15000 targets involved in protein-protein interactions. With the help of corresponding targeting ligands/peptides, these ligands could be coupled to about 1100 linkers (of which about 300 PEG-type linkers), with about 65 ligands for E3 ligase binding. In order to improve the permeability of cells, the inventors further combined the peptide PROTAC technology with about 800 cell-penetrating peptides.

SMILES (Simplified molecular input line entry specification) is a specification that clearly describes the molecular structure with ASCII strings; InChI Key is the abbreviation of International Chemical Identifier, and InCHI code is the unique identification code for the chemical structure of each compound given by the International Union of Pure and Applied Chemistry (IUPAC), and its only corresponding compound can be easily found in the PubMed ChemCompound database (https://www.ncbi.nlm.nih.gov/pccompound) via the InChI key.

Table 1 shows selections of the Linker module, including but not limited to the molecular structures represented by SMILES and the compounds corresponding to the InChI key, as shown in Table 1 below for details.

Smiles InChI Key CCOCCOC CAQYAZNFWDDMIT-UHFFFAOYSA-N CCOCCOCCOCCOC JRRDISHSXWGFRF-UHFFFAOYSA-N CCNC(═O)COCCOCC QETLNMPRYFLOQP-UHFFFAOYSA-N CCNC(═O)COCCOCCOCCOCC PEHBLNOEQICMNP-UHFFFAOYSA-N CCOCCOCC═O VAKGZFIDFWQAJM-UHFFFAOYSA-N CCOCCOCCOCCOCC═O FMXVEMRCLXJCIA-UHFFFAOYSA-N CCOCCOCCOCCOCCOC YZWVMKLQNYGKLJ-UHFFFAOYSA-N CCCCCOCCOC OJTBQXZLANYDLF-UHFFFAOYSA-N CCOCCOCCOC CNJRPYFBORAQAU-UHFFFAOYSA-N COCCOCCOCC═O IGENRCKJLAQXEW-UHFFFAOYSA-N CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N CCOCCOCCOCCOCC KIAMPLQEZAMORJ-UHFFFAOYSA-N CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N CCOCCOCCOCC RRQYJINTUHWNHW-UHFFFAOYSA-N CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N CCCCCOCC VDMXPMYSWFDBJB-UHFFFAOYSA-N CCOCC═O IAHZBRPNDIVNNR-UHFFFAOYSA-N CCOCCOCC═O VAKGZFIDFWQAJM-UHFFFAOYSA-N CCOCCOCCOCC═O VIGPEKUIVIPDAG-UHFFFAOYSA-N CCCCC═O HGBOYTHUEUWSSQ-UHFFFAOYSA-N CCOCCCCC═O BCIRIYVFTVIZSE-UHFFFAOYSA-N O═CCO WGCNASOHLSPBMP-UHFFFAOYSA-N CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N CC OTMSDBZUPAUEDD-UHFFFAOYSA-N CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N C#CCCC IBXNCJKFFQIKKY-UHFFFAOYSA-N C#CCC KDKYADYSIPSCCQ-UHFFFAOYSA-N C#CCOCCOCCOCC NIFIKPHRYNDRRF-UHFFFAOYSA-N C#CCCCCCC UMIPWJGWASORKV-UHFFFAOYSA-N CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N CCCCCOC DBUJFULDVAZULB-UHFFFAOYSA-N CCCN1CCC(CC)CC1 JKHJGIRRPGGIIV-UHFFFAOYSA-N CCCN1CCN(CC)CC1 ZJAQKWSLYRNXDR-UHFFFAOYSA-N CCCC#CC1═CN(CC)N═C1 BDURCJQVOLLHBO-UHFFFAOYSA-N CCC#CC1═CN(C)N═C1 YFZOFEJRYGXPSN-UHFFFAOYSA-N CCCCC1═CN(C)N═C1 QTCJYVJPWUREDL-UHFFFAOYSA-N CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N CCCCCCCCCCC RSJKGSCJYJTIGS-UHFFFAOYSA-N C#CC1═CC═C(CCCCCC)N═C1 JVXALQWTVBJACI-UHFFFAOYSA-N C#CC1═CC═C(N2CCN(CCC)CC2)N═C1 KUIOGLKGGGGIAM-UHFFFAOYSA-N C#CC1═CC═C(N2CCN(CCCC)CC2)N═C1 FCWKVTCLYUQKNS-UHFFFAOYSA-N C#CC1═CC═C(N2CCN(CC)CC2)N═C1 APRHSTGCOUVFGK-UHFFFAOYSA-N C#CC1═CC═C(N2CCN(C)CC2)N═C1 OILUJPMEHSBBQL-UHFFFAOYSA-N C#CC1═CC═C(N2CCNCC2)N═C1 IMSQYOVMMQROAO-UHFFFAOYSA-N C#CC1CCN(C2CCNCC2)CC1 BRIAZNMAVALSCM-UHFFFAOYSA-N CCCCCCCCCNC═O HEIIJVVALRPNFV-UHFFFAOYSA-N CCCCCCCCCCNC═O ZNCRMMYZWDNTCE-UHFFFAOYSA-N CCCCNC(═O)CO WFYNRXPMFUYIDC-UHFFFAOYSA-N CCCCNC(C)═O GYLDXXLJMRTVSS-UHFFFAOYSA-N CCCCCCCO BBMCTIGTTCKYKF-UHFFFAOYSA-N CCCOCC NVJUHMXYKCUMQA-UHFFFAOYSA-N CCCCCNC═O UBKOTQBYKQFINX-UHFFFAOYSA-N NCCN1C═C(CO)N═N1 QBRSPHHAFDKHBS-UHFFFAOYSA-N NCCN1C═C(COCCO)N═N1 MLEHCIIJTRPTGA-UHFFFAOYSA-N NCCN1C═C(COCCOCCO)N═N1 VYVPEKOLZKXSGT-UHFFFAOYSA-N NCCN1C═C(COCCOCCOCCO)N═N1 XNRQJYPYBNBWJK-UHFFFAOYSA-N NCCN1C═C(COCCOCCOCCOCCO)N═N1 CMBXUPPKXOSUED-UHFFFAOYSA-N COCC1═CN(CCN)N═N1 XUQZBMLYINPFHS-UHFFFAOYSA-N COCCOCC1═CN(CCN)N═N1 QPYGOKLPMSIQDN-UHFFFAOYSA-N COCCOCCOCC1═CN(CCN)N═N1 LDNUXLMZQAVQMX-UHFFFAOYSA-N COCCOCCOCCOCC1═CN(CCN)N═N1 VDWXNHBISFHPAI-UHFFFAOYSA-N COCCOCCOCCOCCOCC1═CN(CCN)N═N1 TVAHVEKMLUNMOI-UHFFFAOYSA-N CO OKKJLVBELUTLKV-UHFFFAOYSA-N CCOCCOCCOCCNC(═O)CC DQKOWFBYHIENAP-UHFFFAOYSA-N CCOCCOCCOCCOCCNC(C)═O ATHNQMOBOHHVGV-UHFFFAOYSA-N CCCC1═CN(CCOCCOCCOCCOCC)N═N1 FCKRLESEKMOAAY-UHFFFAOYSA-N CCCC1═CN(CCOCCOCCOCCOCCNC(C)═O)N═N1 LEIGAYMEZRVQMF-UHFFFAOYSA-N CCCCOCCOCCOCC VXVGKMGIPAWMJC-UHFFFAOYSA-N CCCCCCCCCCCOCCCC BFTNUQIEWVRTCA-UHFFFAOYSA-N CCCCCCOCCCCCCOCCCCC QGMIIQRSLFEZNE-UHFFFAOYSA-N CCCCCCCCCOCCCCOCCCC ZRZNGCGNHBPEEW-UHFFFAOYSA-N CCCCCCOCCOCCOCCOCCOCCOCCCCC GBTJHLJNCMMVEE-UHFFFAOYSA-N CCCCCCOCCCCOCCCCOCCCCOCCCCC CCRDSFBIFBOEPO-UHFFFAOYSA-N CCCOCCOCC MZBACIJSSOHXQA-UHFFFAOYSA-N CCCOCCCOCC ZFHCEEOJBANLST-UHFFFAOYSA-N CCCCOCCCCOC FBPKXEFBJHBHJN-UHFFFAOYSA-N CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N CCCOCCOCCC HQSLKNLISLWZQH-UHFFFAOYSA-N CCCOCCCOCCC PZYMDANKTMTEIY-UHFFFAOYSA-N CCCCNC(C)═O GYLDXXLJMRTVSS-UHFFFAOYSA-N CCCCCCCCNC(C)═O GLJKLMQZANYKBO-UHFFFAOYSA-N CCCCCC═O JARKCYVAAOWBJS-UHFFFAOYSA-N CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N CCCOCCOCCOCCCNC(C)═O FCOSMYXPOFLRFY-UHFFFAOYSA-N CCCCCN DPBLXKKOBLCELK-UHFFFAOYSA-N CCOC XOBKSJJDNFUZPF-UHFFFAOYSA-N CC(═O)NCCOCCOCC(═O)NCCOCCO CBFGQJLCZYDUKF-UHFFFAOYSA-N CC(═O)NCCOCCO DJDAFXBIBNKCBR-UHFFFAOYSA-N CC(═O)NCCOCCOCC(═O)NCCOCCOCC(═O)NCCOCCO OWOUJOSDJHEXFQ-UHFFFAOYSA-N NCCOCCOCCOCCN NIQFAJBKEHPUAM-UHFFFAOYSA-N COCCCCOCCCOC1═CC═C(N)C═C1 SINCTDJNRNXKAO-UHFFFAOYSA-N CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N CCOC XOBKSJJDNFUZPF-UHFFFAOYSA-N CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N CCOCCOC CAQYAZNFWDDMIT-UHFFFAOYSA-N CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N CCOCCOCCOCCO WFSMVVDJSNMRAR-UHFFFAOYSA-N CCOCCOCCOCCOC JRRDISHSXWGFRF-UHFFFAOYSA-N CCOCCOCCOCCOCCO GTAKOUPXIUWZIA-UHFFFAOYSA-N CCOCCOCCOCCOCCOC YZWVMKLQNYGKLJ-UHFFFAOYSA-N CCOCCOCCOCCOCCOCCO NJRFAMBTWHGSDE-UHFFFAOYSA-N CCOCCOCCOCCOCCOCCOC PJXDGFJDVVVXCY-UHFFFAOYSA-N OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N OCCOCCOCCOCCOCCOCCO IIRDTKBZINWQAW-UHFFFAOYSA-N CCOCCOCCOCCOCCOCCNC(C)═O CUAFPSUETCCBKZ-UHFFFAOYSA-N CCNC(C)═O PMDCZENCAXMSOU-UHFFFAOYSA-N CCN1C═C(C)N═N1 MJIOJWXRXDWUBV-UHFFFAOYSA-N CCOCCN1C═C(C)N═N1 ZSUBJILEBOCSPA-UHFFFAOYSA-N CCOCCOCCN1C═C(C)N═N1 IUKAVXDFGYPRJN-UHFFFAOYSA-N CCOCCOCCOCCN1C═C(C)N═N1 XYQHQTXKPLBAMW-UHFFFAOYSA-N COCCOCCOCCN OKUWOEKJQRUMBW-UHFFFAOYSA-N CCCCCCCCN IOQPZZOEVPZRBK-UHFFFAOYSA-N CCOCCOCCN KURRHYKFNUZCSJ-UHFFFAOYSA-N CCOCCOCCOC1═CC═C(N)C═C1 ZPPAIDISWIOLFL-UHFFFAOYSA-N CCOCCOCCOC1═CC═CC(N)═C1 JALUOFLXLMYSLF-UHFFFAOYSA-N NCC═O LYIIBVSRGJSHAV-UHFFFAOYSA-N O═CCCC(═O)NCC═O GZVFPGVIQBINMS-UHFFFAOYSA-N O═CCCCC(═O)NCC═O PIJCAVNFNFGLTJ-UHFFFAOYSA-N CCOCCOCCOCCNC(C)═O JOVFTSYTPCENPI-UHFFFAOYSA-N CCOCCOCCOCCNC(═O)CO HQTQBLVLNRHRPZ-UHFFFAOYSA-N CCOCCOCCN1C═C(C═O)N═N1 ZNAOSTXJYFIKBZ-UHFFFAOYSA-N CCOCCOCCOCCN1C═C(C═O)N═N1 YUYIWPLVJSWWGQ-UHFFFAOYSA-N CCOCCOCCOCCOCCN1C═C(C═O)N═N1 YESZEWIOSFYVAA-UHFFFAOYSA-N CCCC1═CN(CCOCCOCC)N═N1 BQZDDUUCYNHBBL-UHFFFAOYSA-N CCOCCOCCOCCN1N═NC═C1C═O ZBCVVBUUELQFGX-UHFFFAOYSA-N CCOCCOCCOCCOCCN1N═NC═C1C═O OFARQSZAAFNSEE-UHFFFAOYSA-N CC(═O)NCCOCCOCCN1C═C(CCCC═O)N═N1 NGHQHEBDKFKOGF-UHFFFAOYSA-N CC(═O)NCCOCCOCCOCCN1C═CN═N1 HAQDEBRMWUNDNK-UHFFFAOYSA-N CC(═O)NCCOCCOCCOCCN1C═C(C═O)N═N1 JIGCWMDYYHPXEW-UHFFFAOYSA-N CC(═O)NCCOCCOCCOCCOCCN1C═C(C═O)N═N1 MADSWKVPPGQVEW-UHFFFAOYSA-N CCCCCCCCCCCN1C═C(C═O)N═N1 JGTUSDGGOIALAA-UHFFFAOYSA-N CCCCCN1C═C(CCCC═O)N═N1 WBYOUGPMCNNHAC-UHFFFAOYSA-N CCCCCN1C═C(C═O)N═N1 SLJXYIVRAZQICO-UHFFFAOYSA-N CCCCCCCC═O NUJGJRNETVAIRJ-UHFFFAOYSA-N COCCOCCOCCO JLGLQAWTXXGVEM-UHFFFAOYSA-N COCCCOCCCCCO XPPFZKCGEIHABQ-UHFFFAOYSA-N COCCCCOC1═CC═CC═C1 JZDHXBGNBZJRFK-UHFFFAOYSA-N CCC(═O)NCCCOCCOCCO ZSOUNYZAIRTFCF-UHFFFAOYSA-N CCCC═O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N CCCCCC═O JARKCYVAAOWBJS-UHFFFAOYSA-N CCCOC VNKYTQGIUYNRMY-UHFFFAOYSA-N CCCOCC NVJUHMXYKCUMQA-UHFFFAOYSA-N CCCOCCC(═O)NCCO ZWZRKLRMHPVSCL-UHFFFAOYSA-N CCOCCOCCC(═O)NCCO CGZNNRDCSGZCCN-UHFFFAOYSA-N CCOCCOCCOCCOCCC(═O)NCCO SESQQSBFFNCJEC-UHFFFAOYSA-N CCCCCOCCOCC UOECJVYWINLCEV-UHFFFAOYSA-N CCCCCOCCCCOCCCC BEGITWDDPUIZSL-UHFFFAOYSA-N O═CCCCNC(═O)CO LNMQGYJLRFKBBM-UHFFFAOYSA-N CCCCCCOCCOCC═O MDCZWRMRSILCQG-UHFFFAOYSA-N CCCCOCCCCOCC═O GAIQORAOHTYFOZ-UHFFFAOYSA-N CCCOCCCOCCC═O DDVUDFQFSHPIKB-UHFFFAOYSA-N CCCOCCCOCCC(═O)NCCO NCLTXMWFZMRLQT-UHFFFAOYSA-N CCCCCCC═O FXHGMKSSBGDXIY-UHFFFAOYSA-N 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CCCNC(═O)CCOCCOCCOCCOCCOCCNC(═O)CCOCCOCCOCC DDCZNDUMQFIGCE-UHFFFAOYSA-N OCCOCC CCCCCCNC(═O)CC WVNFFHLXDXOSGO-UHFFFAOYSA-N CCOCCOCCOCCOCCC(═O)N1CCCCC1 GORQSGKROVUXHB-UHFFFAOYSA-N CCOCCOCCOCCC(═O)N1CCCCC1 IOKWKYZOEBVEBU-UHFFFAOYSA-N CCOCCOCCOCCC(═O)N1CC(C)C1 CUZHEHSKFZQZPO-UHFFFAOYSA-N CCCCCCCCCC(═O)N1CCN(CC2═CC═C(C)C═C2)CC1 XZIZADNFZVHVRR-UHFFFAOYSA-N CCCCCCCCCC(═O)N1CCNCC1 CJFPGCKUAUNMHO-UHFFFAOYSA-N CCCOCCCCOCCCNC(C)═O QXBRTKUNDWWBCM-UHFFFAOYSA-N CCOCC1═CN(CCOCCOCCC═O)N═N1 VRVRIXZCPFKIQB-UHFFFAOYSA-N C#CCOCCOCCOCCOCCC═O NEBHYQIAMLUJDI-UHFFFAOYSA-N OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N OCC1═CN═C(CO)C═N1 HTXOIHGJECPJIU-UHFFFAOYSA-N CCOCCN1C═C(COCC)N═N1 GRLLJNJWRWKWSX-UHFFFAOYSA-N CCOCCOCCOCCN1C═C(COCC)N═N1 YBYSAXFBXHPGBP-UHFFFAOYSA-N CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N CC(═O)NCCCN(C)C(C)C KDDWELLQASOHNW-UHFFFAOYSA-N CC(═O)NCCCCN(C)C(C)C LVBHCIMSCQFXKA-UHFFFAOYSA-N CC(═O)NCCOCCN(C)C(C)C BXCKIGATIPFOMS-UHFFFAOYSA-N CC(═O)NCCOCCOCCN(C)C(C)C WDKNYGIKNAZDNY-UHFFFAOYSA-N CC(═O)NCCOCCOCCOCCN(C)C(C)C MFJGKGROGOLTMK-UHFFFAOYSA-N CC(═O)NCCN(C)C(C)C WFGDITSPCFYUOZ-UHFFFAOYSA-N CCCCN(C)C(C)C KKBDINYFLTTZAQ-UHFFFAOYSA-N CCCN(C)C(C)C OYQDUCLFZSKBCZ-UHFFFAOYSA-N CC(C)N(C)CCCNC(═O)CO GECLTMRIXDTICE-UHFFFAOYSA-N CC(═O)NCCCN(C)C OHLICMMXIJECIN-UHFFFAOYSA-N CCCN(C)CCCNC(C)═O JANJMBPFCYDLQZ-UHFFFAOYSA-N CC(═O)NCCOCCN(C)C NCCAWFFMEPWOOH-UHFFFAOYSA-N CCCN(C)CCOCCNC(C)═O ZFWHIVXUTMRFOV-UHFFFAOYSA-N CC(═O)NCCCN(C)C(C)(C)CCC#N LJNAQLYOVRMQER-UHFFFAOYSA-N CN(C)CCOCCNC(═O)CN IELFBMABZWXVAF-UHFFFAOYSA-N CCCN(C)CCOCCNC(═O)CN WYTCOWNFAQMJJZ-UHFFFAOYSA-N CC(C)N(C)CCOCCNC(═O)CN OOMRMVJYDVKEIA-UHFFFAOYSA-N CCCNC(═O)CC YUMCRXLLWKQDJY-UHFFFAOYSA-N NCCCCCCCC═O GKOPBHPTLGFKOR-UHFFFAOYSA-N NCCCCCCCCCCC═O XSVQSLVVCYRXCL-UHFFFAOYSA-N NCCCCCCCCCCCC═O GDWQVDJDAUJLON-UHFFFAOYSA-N CCCCNC(═O)CO WFYNRXPMFUYIDC-UHFFFAOYSA-N CNC(═O)CCCC═O MGPSVKVFOOVOFZ-UHFFFAOYSA-N O═CCN1CCC(CNC═O)CC1 AYWVMRKDYWNHKQ-UHFFFAOYSA-N O═CCCCC═O SXRSQZLOMIGNAQ-UHFFFAOYSA-N CC1CCN(C═O)CC1 WCKITLGQGJSRBV-UHFFFAOYSA-N NCCCCCC(N)═O ZLHYDRXTDZFRDZ-UHFFFAOYSA-N NCCOCCOCC(N)═O CDFONQZJZPNQML-UHFFFAOYSA-N CCCCCCCCNC(C)═O GLJKLMQZANYKBO-UHFFFAOYSA-N C1CC(CCN2CCNCC2)CCN1 MXTMUSBXYDAXEK-UHFFFAOYSA-N C1CC(OCCN2CCNCC2)CCN1 JXCKBJKSCSVLCY-UHFFFAOYSA-N OCCCCCN1CCNCC1 JQOBQNAVHUEQPB-UHFFFAOYSA-N C1CC(CN2CCN(CC3CCNCC3)CC2)CCN1 CXPVURPCWVRDAG-UHFFFAOYSA-N C1CC(CCN2CCC3(CCNCC3)CC2)CCN1 DILBUBUHQKMCKO-UHFFFAOYSA-N C1CC(CCN2CCC3(CCNCC3)CC2)CCN1 DILBUBUHQKMCKO-UHFFFAOYSA-N C1CC(CN2CCOC3(CCNCC3)CC2)CCN1 BFCQBZFXQYTGJH-UHFFFAOYSA-N C1CC(CCN2CCOC3(CCNCC3)CC2)CCN1 YMEPHYOPKJJPFD-UHFFFAOYSA-N C1CC2(CCN1)CC(CN1CC3(CCNCC3)C1)C2 KMDFIPVKOHKDMJ-UHFFFAOYSA-N C1CC(CN2CCNCC2)CCN1 INUYEZQAQSEPMT-UHFFFAOYSA-N OC1CCC2(CC1)CCN(CC1CCNCC1)CC2 WBRXCBGYGQLNQG-UHFFFAOYSA-N CCOC1═CC═C(CC)C═C1 BQBROHBMIBOPFU-UHFFFAOYSA-N CCCOC1═CC═C(C)C═C1 QLTKVDKXTKKJOX-UHFFFAOYSA-N CCCC1═CC═C(C)C═C1 JXFVMNFKABWTHD-UHFFFAOYSA-N CCC1═CC═C(C)C(F)═C1 DYKMICWOBLSRIW-UHFFFAOYSA-N NCCCNC(═O)CCCCCCNC(═O)CO GXRUEVSAWFUYNL-UHFFFAOYSA-N CCCCCCCC(═O)NCCCN AZGZCTUTODQNFW-UHFFFAOYSA-N CCCCCCCNC(═O)CO BPFGOQULJGPNTD-UHFFFAOYSA-N OCCCCCN1C═C(CN2CCNCC2)N═N1 MTIMZAHMBOLSHZ-UHFFFAOYSA-N OCCN1CCNCC1 WFCSWCVEJLETKA-UHFFFAOYSA-N OCCCN1CCNCC1 LWEOFVINMVZGAS-UHFFFAOYSA-N OCCCCCCN1CCNCC1 RMIIQABTVWHYKA-UHFFFAOYSA-N CCCCN1CCNCC1 YKSVXVKIYYQWBB-UHFFFAOYSA-N CCCCCN1CCNCC1 MJWWNBHUIIRNDZ-UHFFFAOYSA-N CCCCCN1C═C(CN2CCNCC2)N═N1 SPLUTQOUWLEIRU-UHFFFAOYSA-N CCOCCNC(═O)CCOCCOCC RRHXXGGYPBLUBP-UHFFFAOYSA-N CCCN1CCN(CCNC(═O)CCOCCOCC)CC1 FVQKRLOBYKWDEY-UHFFFAOYSA-N O═CNCCCCCCCCNC(═O)CO MLFHWPIWTNJODL-UHFFFAOYSA-N CCOCCOCCOCCOCCC(═O)NC1═CC═CC(C)═C1 WRKJGBIKJXWNON-UHFFFAOYSA-N O═CCCCCCCCNC(═O)CO WIQGTRQGYZGWML-UHFFFAOYSA-N CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N CCOCCOCCNC(═O)CN PHICTDCYZJZWBO-UHFFFAOYSA-N CC(═O)NCCOCCOCCOCCC═O SVZLKBWUDJMXGH-UHFFFAOYSA-N CCOCCNC(C)═O VNVZKKJQVMBZNN-UHFFFAOYSA-N CCCOCCOCCOCCNC(═O)CO DXHOONGGAMPJPN-UHFFFAOYSA-N CCCNC(═O)CCCCCCNC(═O)CO WPFSARBSQPVWDD-UHFFFAOYSA-N O═CCCCCCCNC(═O)CO FBJRVOACVHVTEO-UHFFFAOYSA-N O═C(CO)NCCCCCCC(═O)NCCO CDVOMNZSLUETHP-UHFFFAOYSA-N CCOCCOCCOCCNC(═O)CN DCKAJMRUSXPRRX-UHFFFAOYSA-N CCOCCNC(═O)CN JRKNJYMVYPWZND-UHFFFAOYSA-N CCOCCOCCC(N)═O KMFYAANKBFXERF-UHFFFAOYSA-N CCOCCOCCOCCOCCC(N)═O FZZPLPGZROHDIE-UHFFFAOYSA-N CC(N)═O DLFVBJFMPXGRIB-UHFFFAOYSA-N CCCC(N)═O DNSISZSEWVHGLH-UHFFFAOYSA-N CCCCCC(N)═O ALBYIUDWACNRRB-UHFFFAOYSA-N C#CCCCCCCC OSSQSXOTMIGBCF-UHFFFAOYSA-N CCOCCNC(═O)CCC═O HQNNHAYYQCEVPP-UHFFFAOYSA-N CCOCCOCCNC(═O)CCC═O KDAIXUIQPNUHIR-UHFFFAOYSA-N NCCOCCNC(═O)CCC═O VEEHVJQSYMNZHW-UHFFFAOYSA-N NCCOCCOCCNC(═O)CCC═O KROVULALCQJERG-UHFFFAOYSA-N NCCOCCOCCOCCNC(═O)CCC═O DPXRNKZXXHGWBJ-UHFFFAOYSA-N NCCCOCCOCCOCCCNC(═O)CCC═O RKNUFOYHPXSCQV-UHFFFAOYSA-N CCCCCCCCNC(═O)CCC═O DBDJJJHMJGHNTO-UHFFFAOYSA-N CCCCCCCCCNC(═O)CCC═O JFOFEDMCDUEZAL-UHFFFAOYSA-N CCCCCCCCCCCCNC(═O)CCC═O AYKSXGYVGBZFIU-UHFFFAOYSA-N CCCCCCCCCCCCCNC(═O)CCC═O RUQGAESQCNEDIH-UHFFFAOYSA-N CCCOCCOCCOCCCNC(═O)CO BBDDYLXZIGBXQL-UHFFFAOYSA-N

Table 2 shows selections of another part of the Linker module, namely PEG type linker, including but not limited to the compounds indicated by “name” therein and corresponding to the EnamineStore ID, see Table 2 below for details. Among them, EnamineStore is the compound database (web site as https://www.enaminestore.com/search).

ID Name EN300-25338 2-bromo-4-(2-hydroxyethoxy)benzaldehyde EN300-83836 2-(benzyloxy)ethan-1-ol EN300-24604 N-[3-(benzyloxy)propyl]-2-chloroacetamide EN300-30793 1-bromo-2-(2-bromoethoxy)ethane EN300-42107 3-(2-hydroxyethoxy)-4-methoxybenzoic acid EN300-01038 2-hydroxy-4-propoxybenzaldehyde EN300-41170 4-(4-cyano-2-methoxyphenoxy)butanoic acid EN300-45144 2-[4-(aminomethyl)-2-methoxyphenoxy]ethan-1-ol EN300-53108 2-(4-amino-3-methylphenoxy)ethan-1-ol EN300-59306 2-[4-(aminomethyl)phenoxy]ethan-1-ol hydrochloride EN300-69417 2-[4-(3-cyanopropoxy)phenyl]acetic acid EN300-77411 2-[4-(2-aminoethoxy)phenyl]acetonitrile hydrochloride EN300-91593 methyl 3-(2-aminophenoxy)propanoate hydrochloride EN300-104088 2-(piperidin-4-yloxy)ethan-1-ol EN300-108904 2-(prop-2-yn-1-yloxy)ethan-1-ol EN300-105595 3-(piperidin-4-yloxy)propan-1-ol EN300-106301 methyl 4-[(4-aminonaphthalen-1-yl)oxy]butanoate EN300-108866 methyl[2-(prop-2-yn-1-yloxy)ethyl]amine hydrochloride EN300-75227 4-(2-hydroxyethoxy)benzoic acid EN300-60360 methyl 3-(4-aminophenoxy)propanoate EN300-53019 2-hydroxypropane-1,2,3-tricarboxylic acid; dimethyl ({2-[(2-methylphenyl)(phenyl)methoxy]ethyl})amine EN300-45326 4-(3-aminophenoxy)butanenitrile EN300-109303 1-chloro-3-(2-hydroxyethoxy)propan-2-ol EN300-95947 4-(2-hydroxyethoxy)phenol EN300-84087 2-[2-(aminomethyl)phenoxy]ethan-1-ol EN300-117907 2-(tert-butoxy)ethan-1-ol EN300-125535 2,2,2-trifluoro-N-[2-(2-hydroxyethoxy)ethyl]acetamide EN300-129658 2-(3-aminopropoxy)ethan-1-ol EN300-133893 2-(2-aminoethoxy)acetic acid hydrochloride EN300-135058 [(3-chloropropoxy)methyl]benzene EN300-131583 4-(but-3-yn-1-yloxy)benzoic acid EN300-118560 2-[2-(2-aminoethoxy)ethoxy]ethan-1-amine EN300-138168 3-(2-carboxyethoxy)propanoic acid EN300-130529 2-(4-amino-2-methylphenoxy)ethan-l-ol EN300-140872 tert-butyl N-[1-cyano-3-(propan-2-yloxy)propyl]carbamate EN300-154609 [4-(but-3-yn-1-yloxy)phenyl]methanamine EN300-153872 sodium 2-(2-hydroxyethoxy)acetate EN300-58533 2-[4-(2-aminoethyl)phenoxy]ethan-1-ol EN300-156651 [5-(2-methoxyethoxy)piperidin-3-yl]methanol EN300-173622 methyl 4-butoxy-2-hydroxybenzoate EN300-184469 2-(3-amino-5-methylphenoxy)ethan-1-ol hydrochloride EN300-187795 2-[(2-{2-[(2-hydroxyethyl)sulfanyl]ethoxy}ethyl)sulfanyl]ethan-1-ol EN300-188510 2-{[2-(2-hydroxyethoxy)ethyl]sulfanyl}ethan-1-ol EN300-119687 tert-butyl N-[2-(2-hydroxyethoxy)ethyl]carbamate EN300-115110 3-(benzyloxy)propan-1-ol EN300-200831 2-[2-(methylamino)ethoxy]ethan-1-ol EN300-201578 2-[2-(ethylamino)ethoxy]ethan-1-ol EN300-201781 2-{[4-(aminomethyl)oxan-4-yl]oxy}ethan-1-ol EN300-207948 3-(2-aminoethoxy)propan-1-ol hydrochloride EN300-208106 5-(tert-butoxy)pentanoic acid EN300-205023 tert-butyl N-[2-(2-bromoethoxy)ethyl]carbamate EN300-208387 4-(tert-butoxy)butanoic acid EN300-202642 tert-butyl N-{[4-(2-aminoethoxy)oxan-4-yl]methyl}carbamate EN300-209494 3-(4-aminophenoxy)propan-1-ol EN300-215454 2-(3-propoxypropanamido)pentanedioic acid EN300-202971 tert-butyl N-{2-[2-(2-hydroxyethoxy)ethoxy]ethyl}carbamate EN300-214094 2-[(1-amino-2-methylpropan-2-yl)oxy]ethan-1-ol EN300-222271 3-(2-amino-4-methanesulfonylphenoxy)propan-1-ol EN300-222272 2-(2-amino-4-methanesulfonylphenoxy)ethan-1-ol EN300-219006 N-[2-(2-bromoethoxy)ethyl]acetamide EN300-217925 N-[2-(2-hydroxyethoxy)ethyl]acetamide EN300-234923 2-(3-aminophenoxy)ethan-1-ol EN300-227945 4-(2-hydroxyethoxy)-3-methoxybenzaldehyde EN300-244237 ethyl 2-(2-aminoethoxy)acetate hydrochloride EN300-164412 2-[2-(aminomethyl]phenoxy]ethan-1-amine dihydrochloride EN300-74512 5-(3-cyanophenoxy)pentanoic acid EN300-75370 3-(4-aminophenoxy)propanoic acid hydrochloride EN300-116457 2-(2-bromoethoxy)ethan-1-ol EN300-253397 [2-(2-aminoethoxy)ethyl](ethyl)amine EN300-258081 2-(azetidin-3-yloxy)ethan-1-ol EN300-257374 4-(4-chlorobutoxy)butan-1-ol EN300-256898 2-[(4-aminophenyl)methoxy]ethan-1-ol EN300-257274 2-(4-hydroxybutoxy)benzaldehyde EN300-266067 (1s,3s)-3-[2-(tert-butoxy)ethoxy]cyclobutan-1-ol EN300-264061 propyl (3S)-3-(aminomethyl)-5-methylhexanoate hydrochloride EN300-298869 2-{[3-(aminomethyl)oxolan-3-yl]oxy}ethan-1-ol EN300-142192 2-(2-azidoethoxy)ethan-1-ol EN300-297883 2-[2-(3-aminopropoxy)ethoxy]ethan-1-ol EN300-298653 2-(2-iodoethoxy)ethan-1-ol EN300-299042 tert-butyl N-{3-[2-(2-hydroxyethoxy)ethoxy]propyl}carbamate EN300-312631 3-fluoro-4-(2-hydroxyethoxy)benzaldehyde EN300-315819 tert-butyl N-methyl-N-{2-[2-(methylamino)ethoxy]ethyl}carbamate EN300-315965 2-({2-[2-(2-{[(tert-butoxy)carbonyl]amino}ethoxy)ethoxy]ethyl}amino)acetic acid EN300-312945 1-bromo-3-(3-bromopropoxy)propane EN300-317293 tert-butyl N-[3-(2-aminoethoxy)propyl]carbamate EN300-332506 1-bromo-4-(4-bromobutoxy)butane EN300-315510 4-amino-3-(2-hydroxyethoxy)benzoic acid EN300-345187 5-(5-amino-2-methylphenoxy)pentan-1-ol EN300-365537 3-{[2-(2,2-dimethylpropanamido)acetyl]oxy}propanoic acid EN300-370460 2-[3-(2-aminoethoxy)phenyl]acetic acid hydrochloride EN300-19706 1-chloro-2-[2-(2-chloroethoxy)ethoxy]ethane EN300-19916 2-[2-(2-hydroxyethoxy)ethoxy]ethan-1-ol EN300-378267 2-{2-[(2-aminoethyl)(methyl)amino]ethoxy}ethan-1-ol EN300-398865 2-{[1-(aminomethyl)-4-(difluoromethyl)cyclohexyl]oxy}ethan-1-ol hydrochloride EN300-686899 3-(prop-2-yn-1-yloxy)propan-1-ol EN300-247320 tert-butyl 2-[2-(2-aminoethoxy)ethoxy]acetate EN300-1067029 3-[2-(tert-butoxy)ethoxy]propanoic acid EN300-814287 2-(2-chloroethoxy)acetyl chloride EN300-104458 2-(2-chloroethoxy)acetic acid EN300-171481 2-[1-(aminomethyl)cyclobutoxy]ethan-1-ol EN300-20351 2-[2-(carboxymethoxy)ethoxy]acetic acid EN300-1091618 2-{[1-(aminomethyl)cyclohexyl]oxy}ethan-1-ol EN300-1178083 2-{[4-(aminomethyl)thian-4-yl]oxy}ethan-1-ol EN300-192866 {[2-(2-chloroethoxy)ethoxy]methyl}benzene EN300-1293808 2-{[3-(aminomethyl)thiolan-3-yl]oxy}ethan-1-ol EN300-52813 2-[4-amino-3-(trifluoromethyl)phenoxy]ethan-1-ol EN300-1588524 2-[2-(aminooxy)ethoxy]ethan-1-ol EN300-1658972 O-[2-(prop-2-yn-1-yloxy)ethyl]hydroxylamine EN300-1609001 3-(aminomethyl)-3-(2-hydroxyethoxy)-llambda6-thiolane-1,1-dione hydrochloride EN300-1700498 2-(3-aminopropoxy)acetic acid hydrochloride EN300-1696667 3-hydroxy-4-propoxybenzaldehyde EN300-1603980 4-amino-2-{2-[2-(2-methoxyethoxy)ethoxy]ethyl}butanoic acid EN300-1704639 2-[2-(benzyloxy)ethyl]propane-1,3-diol EN300-1700367 rac-2-{[(2R,6R)-6-methylpiperidin-2-yl]methoxy}ethan-1-ol EN300-1719373 methyl 3-(2-aminoethoxy)propanoate hydrochloride EN300-298890 butyl 2-(aminooxy)acetate EN300-384462 4-(benzyloxy)-2,2-dimethylbutan-1-ol EN300-7440871 12-bromo-2,2,3,3-tetramethyl-4,7,10-trioxa-3-siladodecane EN300-207151 1-[2-(2-aminoethoxy)ethoxyl-2-(2-azidoethoxy)ethane EN300-207147 2-[2-(2-azidoethoxy)ethoxy]ethan-1-ol EN300-74137 2-(4-aminophenoxy)ethan-1-ol EN300-6948257 2-(but-3-yn-1-yloxy)acetic acid EN300-6963624 2-[2-(prop-2-yn-1-yloxy)ethoxy]acetic acid EN300-305336 1-phenyl-2,5,8,11-tetraoxatridecan-13-ol EN300-27187326 sodium 2-[6-(4-ethynylphenoxy)hexyl]oxirane-2-carboxylate EN300-7403031 3,6,9,12,15,18,21,24-octaoxahexacosane-1,26-diol EN300-7492463 sodium 2-(2-hydroxyethoxy)ethane-1-sulfonate EN300-7472919 tert-butyl N-{[4-(2-aminoethoxy)oxan-4-yl]methyl}carbamate hydrochloride EN300-6474931 2-(2-aminoethoxy)phenol hydrochloride EN300-7493941 4-[4-(hydroxymethyl)-2-methoxy-5-nitrophenoxy]butanoic acid EN300-26698161 methyl 4-[(1,3-dihydroxypropan-2-yl)oxy]butanoate EN300-6986641 3-[2-(2-aminoethoxy)ethoxy]prop-1-yne EN300-7462425 2-{2-[2-(prop-2-yn-1-yloxy)ethoxy]ethoxy}acetic acid EN300-6493675 tert-butyl N-(2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ethyl)carbamate EN300-174976 3-(tert-butoxy)propan-1-ol EN300-7468960 2-[4-(prop-2-yn-1-yloxy)butoxy]acetic acid EN300-2008265 N-{2-[2-(2-azidoethoxy)ethoxy]ethyl}-2-iodoacetamide EN300-1264318 tert-butyl 4-(2-hydroxyethoxy)piperidine-1-carboxylate EN300-6476878 2-[2-(piperazin-1-yl)ethoxy]ethan-1-ol EN300-2009274 3-(2-hydroxyethoxy)-4-methoxybenzaldehyde EN300-7541483 3-[(oxiran-2-yl)methoxy]propan-1-ol EN300-7541876 2-aminoethyl 2-cyanoacetate hydrochloride EN300-137387 2-[2-(2-aminoethoxy)ethoxy]ethan-1-ol EN300-226150 2-{2-[(2-aminoethyl)amino]ethoxy}ethan-1-ol EN300-6482855 2-[(1-amino-3,3-dimethylbutan-2-yl)oxy]ethan-1-ol hydrochloride EN300-6496816 tert-butyl N-[2-(2-aminoethoxy)ethyl]carbamate hydrochloride EN300-6497222 2-[2-(aminomethyl)phenoxy]ethan-1-ol hydrochloride EN300-6498752 4-(2-aminoethoxy)-3-methoxyphenol hydrochloride EN300-247319 tert-butyl 2-[2-(2-aminoethoxy)ethoxy]acetate hydrochloride EN300-6728975 2-(2-aminophenoxy)ethan-1-ol hydrochloride EN300-7016274 3-(3-chloropropoxy)propan-1-ol EN300-6494414 2-(2-hydroxyethoxy)ethyl formate EN300-6746213 2-(2-bromoethoxy)ethan-1-amine hydrobromide EN300-6734328 2-(2-chloroethoxy)-2-methylpropanoic acid EN300-6746825 5-(2-hydroxyethoxy)pentan-1-ol EN300-384559 4-[(2-hydroxyethoxy)methyl]piperidin-4-ol hydrochloride EN300-6738369 2-(3-bromopropoxy)ethan-1-amine hydrobromide EN300-192867 2-[2-(benzyloxy)ethoxy]ethan-1-ol EN300-7431084 3-(3-aminopropoxy)propan-1-ol hydrochloride EN300-317133 2-{2-[2-(benzyloxy)ethoxy]ethoxy}ethan-1-ol EN300-7354186 2-[(piperidin-4-yl)methoxy]ethan-1-ol hydrochloride EN300-6730172 tert-butyl N-[2-(3-aminopropoxy)ethyl]carbamate EN300-6748987 2-[(2-hydroxyethoxy)carbonyl]benzoic acid EN300-6746824 3-(2-hydroxyethoxy)-2-methylpropan-1-ol EN300-1472331 2-{2-[4-(2-{[2-(2-aminoethoxy)ethyl]amino}ethyl)piperazin-1-yl]ethoxy}ethan-1-amine EN300-1655786 [2-(2-chloroethoxy)ethyl]phosphonic acid EN300-6764893 2-(pyrrolidin-3-yloxy)ethan-1-ol hydrochloride EN300-315500 4-amino-3-(3-hydroxypropoxy)benzoic acid EN300-19202 1-chloro-2-(2-chloroethoxy)ethane EN300-244444 2-{2-[2-(2-azidoethoxy)ethoxy]ethoxy}ethan-1-ol EN300-7438426 tert-butyl[2-(2-iodoethoxy)ethoxy]dimethylsilane EN300-7441287 {1-[2-(benzyloxy)ethyl]piperidin-4-yl}methanol hydrochloride EN300-7360457 3-(2-aminoethoxy)benzoic acid hydrochloride EN300-263879 2,2,3,3-tetramethyl-4,7,10-trioxa-3-siladodecan-12-ol EN300-7460414 tert-butyl N-[2-(2-aminoethoxy)phenyl]carbamate hydrochloride EN300-7459316 O-{6-[3,5-bis(chloromethyl)phenoxy]hexyl}hydroxylamine; trifluoroacetic acid EN300-761318 2-(pent-4-yn-1-yloxy)acetic acid EN300-7353728 3-[2-(2-chloroethoxy)ethoxy]propan-1-ol EN300-7411332 1-iodo-2-(2-iodoethoxy)ethane EN300-7417011 2-{2-[2-(prop-2-yn-1-yloxy)ethoxy]ethoxy}ethan-1-ol EN300-7435275 ({2-[2-(2-bromoethoxy)ethoxy]ethoxy}methyl)benzene EN300-7465452 5-(2-aminoethoxy)-2-fluorobenzoic acid hydrochloride EN300-1694009 chloro[2-(prop-2-yn-1-yloxy)ethoxy]methanone EN300-1294256 2-[(1-amino-3-methylbutan-2-yl)oxy]ethan-1-ol EN300-7456815 4-(2-{[4-(tert-butoxy)-4-oxobutanoyl]oxy}ethoxy)-4-oxobutanoic acid EN300-7443005 12-iodo-2,2,3,3-tetramethyl-4,7,10-trioxa-3-siladodecane EN300-19499 2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ethan-1-ol EN300-16700 2-(2-hydroxyethoxy)phenol EN300-134537 2-[2-(2-chloroethoxy)ethoxy]ethan-1-ol EN300-7427656 14-amino-3,6,9,12-tetraoxatetradecan-1-ol hydrochloride EN300-157830 2-(piperidin-3-yloxy)ethan-1-ol hydrochloride EN300-245588 tert-butyl 3-(2-hydroxyethoxy)propanoate EN300-344268 [2-(2-chloroethoxy)ethyl](methyl)amine hydrochloride EN300-7471137 sodium 5-(2-aminoethoxy)-2-chlorobenzoate EN300-7440874 2-[4-(bezyloxy)butoxy]ethan-1-ol EN300-1587973 2-{[1-(aminomethyl)cyclopentyl]oxy}ethan-1-ol hydrochloride EN300-1589200 2-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}ethan-1-ol EN300-7463738 2-{2-[2-(2-chloroethoxy)ethoxy]ethoxy}ethan-1-ol EN300-6477608 2-[2-(2-hydroxyethoxy)ethoxy]acetic acid EN300-7549881 5-(2-aminoethoxy)-2-methylbenzoic acid hydrochloride EN300-7549176 3-(3-aminopropoxy)benzoic acid hydrochloride EN300-7549473 3-(2-aminoethoxy)-4-methylbenzoic acid hydrochloride EN300-7563216 2-{2-[4-(azetidin-3-yl)piperazin-1-yl]ethoxy}ethan-1-ol dihydrochloride EN300-7562783 lithium(1+) 3-(3-hydroxypropoxy)propanoate EN300-7549954 3-(2-aminoethoxy)-2-methylbenzoic acid hydrochloride EN300-24791881 3-(3-azidopropoxy)propan-1-ol EN300-7500523 2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}acetic acid EN300-26619695 2-(2-aminoethoxy)-3-methoxyphenol hydrochloride EN300-7348271 2-[2-(prop-2-yn-1-yloxy)ethoxy]ethan-1-ol EN300-7545089 3-[2-(3-chloropropoxy)ethoxy]propan-1-ol EN300-7440875 tert-butyl[4-(2-iodoethoxy)butoxy]dimethylsilane EN300-22991138 4-[3-(4-azidobutoxy)propoxy]butan-1-ol EN300-105617 4-(benzyloxy)butan-1-ol EN300-26860934 2-(methylamino)ethyl 2-cyanoacetate hydrochloride EN300-26675060 3-[2-(3-aminopropoxy)ethoxy]propan-1-ol hydrochloride EN300-7563169 4-(4-azidobutoxy)butan-1-ol EN300-7461359 4-[3-(4-hydroxybutoxy)propoxy]butan-1-ol EN300-6490355 4,7,10,13-tetraoxahexadec-15-ynoic acid EN300-22991137 3-[2-(3-azidopropoxy)ethoxy]propan-1-ol EN300-6493668 tert-butyl 3-[2-(2-aminoethoxy)ethoxylpropanoate EN300-22991140 4-[3-(4-hydroxybutoxy)propoxy]butanoic acid EN300-26286168 1-(2-aminoethoxy)-2-(2-azidoethoxy)ethane hydrochloride EN300-23254233 3-(2-{2-[2-(3-formyl-2-hydroxyphenoxy)ethoxy]ethoxy]ethoxy)-2-hydroxybenzaldehyde EN300-227949 3-ethoxy-4-(2-hydroxyethoxy)benzaldehyde EN300-22991136 4-[3-(4-chlorobutoxy)propoxy]butan-1-ol EN300-7472215 3-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}prop-1-yne hydrochloride EN300-7373222 4,7,10,13,16-pentaoxanonadec-18-ynoic acid EN300-7086397 4-(prop-2-yn-1-yloxy)butan-1-ol EN300-6491579 3,6,9,12-tetraoxapentadec-14-yn-1-amine EN300-7441482 3-hydroxy-4-(2-methoxyethoxy)benzaldehyde EN300-53715 2-(2-amino-5-fluorophenoxy)ethan-1-ol EN300-109693 2-[(oxiran-2-yl)methoxy]ethan-1-ol EN300-20950 2-(2-aminoethoxy)ethan-1-ol EN300-7420955 1-azido-2-[2-(2-bromoethoxy)ethoxy]ethane EN300-298437 2-{[1-(aminomethyl)-4,4-difluorocyclohexyl]oxy}ethan-1-ol EN300-7624053 3-(prop-2-yn-1-yloxy)propan-1-amine hydrochloride EN300-26673732 methyl 3-[2-(2-aminoethoxy)ethoxy]propanoate hydrochloride EN300-343270 methyl 4-amino-3-(2-hydroxyethoxy)benzoate hydrochloride EN300-300233 3-{[2-(tert-butoxy)ethyl]amino}propanoic acid EN300-315506 4-amino-3-(4-hydroxybutoxy)benzoic acid EN300-145574 3-(4-aminophenoxy)propanoic acid EN300-1719224 3-(2-aminoethoxy)propanoic acid hydrochloride EN300-746601 4-(2-aminoethoxy)benzoic acid hydrochloride EN300-213748 [(3-bromopropoxy)methyl]benzene EN300-108377 [(2-bromoethoxy)methyl]benzene EN300-317578 tert-butyl N-{2-[2-(methylamino)ethoxy]ethyl}carbamate EN300-77716 methyl 4-[4-(aminomethyl)phenoxy]butanoate hydrochloride EN300-1709680 2-(2-azidoethoxy)ethan-1-amine hydrochloride EN300-315817 tert-butyl N-[2-(2-aminoethoxy)ethyl]-N-methylcarbamate EN300-208938 3-(2-{[(tert-butoxy)carbonyl]amino}ethoxy)propanoic acid EN300-74705 2-(2-{[(tert-butoxy)carbonyl]amino}ethoxy)acetic acid EN300-74728 methyl 4-(4-aminophenoxy)butanoate hydrochloride EN300-157099 methyl 2-(2-aminoethoxy)acetate hydrochloride EN300-1704345 tert-butyl N-{2-[2-(2-aminoethoxy)ethoxy]ethyl}carbamate EN300-209079 {2-[(3-carboxypropanoyl)oxy]ethyl}trimethylazanium chloride EN300-1721470 5-(2-hydroxyethoxy)pentanoic acid EN300-22054521 3-[2-(3-hydroxypropoxy)ethoxy]propanoic acid EN300-736822 2-acetamidoethyl (3S)-3-(aminomethyl)-5-methylhexanoate hydrochloride EN300-1165943 disodium 2-[2-(carboxymethoxy)ethoxy]acetate EN300-1266169 bis((2E)-but-2-enedioic acid); 3-ethyl 5-methyl 2,6-bis[(2-aminoethoxy)methyl]- 4-(2-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylate EN300-6736929 2-(3-chloropropoxy)ethan-1-amine hydrochloride EN300-383885 3-{2-[2-(3-aminopropoxy)ethoxy]ethoxy}propan-1-amine EN300-7426195 4-(2-hydroxyethoxy)butan-1-ol EN300-7378103 2-(2-{[2-(2-hydroxyethoxy)ethyl]amino}ethoxy)ethan-1-ol EN300-1723415 2-(2,5-dioxopyrrolidin-1-yl)ethyl (3S)-3-(aminomethyl)-5-methylhexanoate hydrochloride EN300-19318 2-(2-hydroxyethoxy)ethan-1-ol EN300-54211 2-[2-({5-[2-(2-hydroxyethoxy)ethoxy]naphthalen-1-yl}oxy)ethoxy]ethan-1-ol EN300-258766 3,6,9,12-tetraoxatetradecane-1,14-diol EN300-298141 2-methoxyethyl (3S)-3-(aminomethyl)-5-methylhexanoate; trifluoroacetic acid EN300-106544 4-[(4-aminonaphthalen-1-yl)oxy]butanenitrile EN300-306385 [2-(2-aminoethoxy)ethyl](methyl)amine EN300-71579 propyl 3-aminopropanoate hydrochloride EN300-246911 2-(propan-2-yloxy)ethyl 3-(aminomethyl)-5-methylhexanoate; trifluoroacetic acid EN300-252444 2-{[2-(2-hydroxyethoxy)ethyl]amino}ethan-1-ol EN300-252599 2-{2-[bis(2-hydroxyethyl)amino]ethoxy}ethan-1-ol EN300-316362 2-(2-aminoethoxy)ethan-1-amine EN300-10061 2-(2-chloroacetamido)ethyl 2-chloroacetate EN300-222334 tert-butyl N-(2-{[2-(2-hydroxyethoxy)ethyl]amino}ethyl)carbamate EN300-7414647 hexyl 5-amino-4-oxopentanoate hydrochloride EN300-6976741 2-(but-3-yn-1-yloxy)propanoic acid EN300-134148 2-(prop-2-yn-1-yloxy)ethan-1-amine hydrochloride EN300-203531 3-(2-aminoethoxy)propan-1-ol EN300-52467 2-(2-chloroethoxy)ethan-1-ol EN300-231011 2-(2-aminophenoxy)ethan-1-ol EN300-6493684 2-{2-[2-(2-{[(tert-butoxy)carbonyl]amino}ethoxy)ethoxy]ethoxy}acetic acid EN300-6493687 3-[2-(2-{[(tert-butoxy)carbonyl]amino}ethoxy)ethoxy]propanoic acid EN300-6493658 tert-butyl N-(2-{2-[2-(2-azidoethoxy)ethoxy]ethoxy}ethyl)carbamate EN300-6493693 tert-butyl N-(2-{2-[2-(2-bromoethoxy)ethoxy]ethoxy}ethyl)carbamate EN300-27736133 2-[(1-amino-2-methylpropan-2-yl)oxy]ethan-1-ol hydrochloride EN300-104201 3-(2-hydroxyethoxy)propan-1-ol EN300-7425446 2-(2-aminoethoxy)-6-methoxyphenol hydrochloride EN300-27702276 lithium(1+) 5-(2-hydroxyethoxy)pentanoate EN300-226100 3,6,9,12,15-pentaoxaheptadecane-1,17-diol EN300-118233 3-(prop-2-yn-1-yloxy)propanoic acid EN300-27719669 tert-butyl N-[2-(2-aminoethoxy)-2-methylpropyl]carbamate hydrochloride EN300-42227 2-(5-amino-2-methoxyphenoxy)ethan-1-ol EN300-8332618 tert-butyl 2-(3-hydroxypropoxy)acetate EN300-1590283 3,6,9,12,15,18,21-heptaoxatricosane-1,23-diol EN300-1706889 2-{2-[2-(2-bromoethoxy)ethoxy]ethoxy}ethan-1-ol EN300-27780250 2-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}ethan-1-ol hydrochloride EN300-6493670 tert-butyl 3-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}propanoate EN300-7398805 2-(2-aminoethoxy)ethan-1-amine dihydrochloride EN300-27721120 tert-butyl N-15-(prop-2-yn-1-yloxy)pentyl]carbamate EN300-7406235 14-azido-3,6,9,12-tetraoxatetradecan-1-ol EN300-316286 tert-butyl N-(2-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}ethyl)carbamate EN300-27082270 1-chloro-3-(2-chloroethoxy)propan-2-one EN300-7364909 2-(4-aminophenoxy)ethan-1-ol hydrochloride EN300-7421448 tert-butyl 3-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}propanoate

Table 3 shows selections of the ligand module for E3 ligase binding, including but not limited to the molecular structures represented by SMILES and the compounds corresponding to the InChI key, as shown in Table 3 below for details.

Sm1les InChI Key CN[C@@H](C)C(═O)N[C@H](C(═O)N1CC2═CC═CC═C2C[C@H]1C(═O)N[C@@H]1CC ATYRKWQJUXHQEF- CC2═CC═CC═C21)C(C)(C)C QNMIOERPSA-N NC1═CC═CC2═C1C(═O)N(C1CCC(═O)NC1═O)C2═O UVSMNLNDYGZFPF- UHFFFAOYSA-N O═C1CCC(N2C(═O)C3═CC═CC═C3C2═O)C(═O)N1 UEJJHQNACJXSKW- UHFFFAOYSA-N NC1═CC═CC2═C1CN(C1CCC(═O)NC1═O)C2═O GOTYRUGSSMKFNF- UHFFFAOYSA-N CC(═O)N[C@H](C(═O)N1C[C@H](O)[C@@H](F)[C@H]1C(═O)NCC1═CC═C(C2═C(C) MNNVXLLCYGGFOQ- N═CS2)C═C1)C(C)(C)C YOUFYPILSA-N NC1═CC═CC2═C1C(═O)N(C1CCC(═O)NC1═O)N═N2 DXZBHVQOULDEPN- UHFFFAOYSA-N CC(═O)N[C@@H](CC1═CC═CC═C1)C(═O)N[C@H](C(═O)N1C[C@H](O)C[C@H]1C ALYDGEQICGMVIP- (═O)NCC1═CC═C(C2═C(C)N═CS2)C═C1)C(C)(C)C UYIZUTNXSA-N NS(═O)(═O)C1═CC═C(S(═O)(═O)NC2═CC═CC3═C2[NH]C═C3Cl)C═C1 SETFNECMODOHTO- UHFFFAOYSA-N COC1═CC═C(C2═NC(C3═CC═C(C1)C═C3)C(C3═CC═C(C1)C═C3)N2C(═O)N2CCNC BDUHCSBCVGXTJM- (═O)C2)C(OC(C)C)═C1 UHFFFAOYSA-N COC1═CC(C(═O)O)═CC═C1NC(═O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N) TVTXCJFHQKSQQM- (C2═CC═C(C1)C═C2F)[C@H]1C1═CC═CC(C1)═C1F LJQIRTBHSA-N CCOC1═CC(C(C)(C)C)═CC═C1C1═N[C@@](C)(C2═CC═C(C1)C═C2)[C@@](C) QBGKPEROWUKSBK- (C2═CC═C(C1)C═C2)N1C(═O)N1CCN(CCCS(O(═O)═O)CC1 QPPIDDCLSA-N CC(═O)N[C@H](C(═O)N1C[C@H](O)C[C@H]1C(═O)NCC1═CC═C(C2═C(C)N═CS2) GFVIEZBZIUKYOG- C═C1)C(C)(C)C SVFBPWRDSA-N CC1═C(C2═CC═C(CNC(═O)[C@@H]3C[C@@H](O)CN3C(═O)[C@@H](NC(═O)C3 NDVQUNZCNAMROD- (C#N)CC3)C(C)(C)C)C═C2)SC═N1 RZUBCFFCSA-N CC1═C(C2═CC═C(CNC(═O)[C@@H]3C[C@@H](O)CN3C(═O)[C@@H](NC(═O)C3(F)C GFNCBUDQFXZVNN- C3)C(C)(C)C)C═C2)SC═N1 SVFBPWRDSA-N CC(═O)N[C@H](C(═O)N1C[C@H](O)C[C@H]1C(═O)N[C@@H](C)C1═CC═C(C2═C(C) JAHUHEDUDMTTTF- N═CS2)C═C1)C(C)(C)C COWZOJLOSA-N CC(═O)N[C@HJ(C(═O)N1C[C@H](O)[C@H](F)[C@H]1C(═O)NCC1═CC═C(C2═C(C) MNNVXLLCYGGFOQ- N═CS2)C═C1)C(C)(C)C VNYTWHDVSA-N CC(═O)N[C@H](C(═O)N1C[C@H](O)C[C@H]1C(═O)N[C@@H](C)C1═CC═C(C1)C═C1) QORQDSURGXKKLU- C(C)(C)C PSMGESJCSA-N CC(═O)N[C@H](C(═O)N1C[C@H](O)C[C@H]1C(═O)N[C@@H](C)C1═CC═C(C#N) OXUULQVWMAOYDZ- C═C1)C(C)(C)C NUDXDXSLSA-N C#CC1═CC═C([C@H](C)NC(═O)[C@@H]2C[C@@H](O)CN2C(═O)[C@@H](NC(C)═O) WHTWICJCWCIKHM- C(C)(C)C)C═C1 WEFJBSGNSA-N CC(═O)N[C@H](C(═O)N1C[C@H](O)C[C@H]1C(═O)N[C@@H](C)C1═CC═C(C2CC2) CFQQOSHEPDRZSL- C═C1)C(C)(C)C MYDCNYLUSA-N CC(═O)N[C@H](C(═O)N1C[C@H](O)C[C@H]1C(═O)N[C@@H](C)C1═CC═C(C(C)C) FPHVSWUJMFIEOJ- C═C1)C(C)(C)C PSMQTCRGSA-N CC(═O)N[C@H](C(═O)N1C[C@H](O)C[C@H]1C(═O)N[C@@H](C)C1═CC═C(C(C)(C)C) HWRVUOLZBZRHRB- C═C1)C(C)(C)C PSMQTCRGSA-N CNC(═O)C[C@H](NC(═O)[C@@H]lC[C!i@H](O)CN1C(═O)[C@@H](NC(C)═O)C(C)(C) DHJHMRSRAVXNPQ- C)C1═CC═C(C2═C(C)N═CS2)C═C1 MDAIXWLXSA-N CNC(═O)C[C@H](NC(═O)(C@@H]1C[C@@H)(O)CN1C(═O)[C@@H](C1═CC(C)═NO1) BUFJKORGWVCZBG- C(C)C)C1═CC═C(C2═C(C)N═CS2)C═C1 HXKBJWFLSA-N CNC(═O)C[C@H](NC(═O)[C@@H]1C[C@@H](O)CN1C(═O)[C@@H](NC(═O)C1(F) PTPPMFQIIPBSRV- CC1)C(C)(C)C)C1═CC═C(C2═C(C)N═CS2)C═C1 MDAIXWLXSA-N CNC(═O)C[C@H](NC(═O)[C@@H]1C[C@@H](O)CN1C(═O)[C@@H](NC(═O)C1(C#N)C TXOUIGUFBKWBLO- C1)C(C)(C)C)C1═CC═C(C2═C(C)N═CS2)C═C1 HXKBJWFLSA-N CNC(═O)C[C@@H1(NC(═O)[C@@H]1C[C@@H)(O)CN1C(═O)[C@@H](NC(═O)C1(F)C PTPPMFQIIPBSRV- C1)C(C)(C)C)C1═CC═C(C2═C(C)N═CS2)C═C1 IUBSTNSRSA-N CNC(═O)C[C@H](NC(═O)[C@@H][C@@H](O)CN1C(═O)[C@H](NC(═O)C1(F)CC1)C PTPPMFQIIPBSRV- (C)(C)C)C1═CC═C(C2═C(C)N═CS2)C═C1 XBJMDHIQSA-N CC1═C(C2═CC═C(CNC(═O)[C@@H]3C[C@@H](O)CN3C(═O)[C@H](C(C)C)N3CC4═CC HEDFFPYRFJKXQP- ═CC═C4C3═O)C═C2)SC═N1 VJTSUQJLSA-N C#CC1═CC═C([C@H](CC(═O)NC)NC(═O)[C@@H]2C[C@@H](O)CN2C(═O)[C@@H] RILDEXHTOOMQCV- (C2═CC(C)═NO2)C(C)C)C═C1 MDAIXWLXSA-N CNC(═O)C[C@H1(NC(═O)[C@@H]1C[C@@H](O)CN1C(═O)[C@@H1(C1═CC(C)═NO1) GEWZUXIXBYUKKN- C(C)C)C1═CC═C(C#N)C═C1 QTDGGUCWSA-N CNC(═O)C[C@HJ(NC(═O)[C@@H]1C[C@@H](O)CN1C(═O)[C@@H](C1═CC(C)═NO1) DZVFTEQNLPBNLU- C(C)C)C1═CC═C(Br)C═C1 MDPIYQRISA-N CNC(═O)C[C@H](NC(═O)[C@@H]1C[C@@H](O)CN1C(═O)[C@@H](C1═CC(C)═NO1) AVTUCSSCVXIPKR- C(C)C)C1═CC═C(C1)C═C1 MDPIYQRISA-N CNC(═O)C[C@H](NC(═O)[C@@H]1C[C@@H](O)CN1C(═O)[C@@H](C1═CC(C)═NO1) QOVORLCCBWSWNE- C(C)C)C1═CC═C(F)C═C1 MDPIYQRISA-N CNC(═O)C[C@H](NC(═O)[C@@H]1C[C@@H](O)CN1C(═O)[C@@H1(C1═CC(C)═NO1) YRJWYFLCJKATIJ- C(C)C)C1═CC═CC═C1 MDPIYORISA-N CNC(═O)C[C@HJ(NC(═O)[C@@H]1C[C@@H](O)CN1C(═O)[C@@H](NC(C)═O)C(C)C) UEIQRCHIEZGBTN- C1═CC═CC═C1 LXZJYRNTSA-N COC1═CC═C(C2═N[C@H](C3═CC═C(C1)C═C3)[C@H](C3═CC═C(C1)C═C3)N2C(═O) BDUHCSBCVGXTJM- N2CCNC(═O)C2)C(OC(C)C)═C1 IZLXSDGUSA-N CC(C)C[C@H](NC(═O)[C@@H](O)[C@H](N)CC1═CC═CC═C1)C(═O)O VGGGPCQERPFHOB- RDBSUJKOSA-N CN[C@@H](C)C(═O)N[C@H](C(═O)N1C[C@@H](N)C[C@H]1C(═O)NC1═C(F)C═CC═C1F) QESAPZFIIYNQSO- C(C)(C)C WXRXAMBDSA-N CN[C@@H](C)C(═O)N[C@H](C(═O)N1CCC[C@H]1C(═O)N[C@@H]1CCCC2═CC═CC═C21) NJUHOYLCAHNNLJ- C1CCCCC1 QODFHFCMSA-N COC1═CC═C2C(═C1)CCCN2C(═O)CC1 XJPUWRWIBSSPSL- UHFFFAOYSA-N O═C1C═C(C2═CC═CC═C2)OC2═CC═C3C═CC═CC3═C12 OUGIDAPQYNCXRA- UHFFFAOYSA-N O═C1C═C(C2═CC═CC═C2)OC2═C1C═CC1═CC═CC═C12 VFMMPHCGEFXGIP- UHFFFAOYSA-N COC(═O)C1═CSC(C(═O)C2═C[NH]C3═CC═CC═C23)═N1 KDDXOGDIPZSCTM- UHFFFAOYSA-N CN[C@@H](C)C(═O)N[C@H](C(═O)N1CCC[C@H]1C1═NC(C(═O)C2═CC═C(F)C═C2)═C JIOIGDQISXGQSO- S1)C1CCN(C)CC1 SSKFGXFMSA-N COC1═CC═C(C2═N[C@@H](C3═CC═C(C1)C═C3)[C@@H](C3═CC═C(C1)C═C3)N2C BDUHCSBCVGXTJM- (═O)N2CCNC(═O)C2)C(OC(C)C)═C1 WUFINQPMSA-N CN[C@@H](C)C(═O)N[C@H](C(═O)N1CCC[C@H]1C(═O)N[C@H](C(═O)OC)C UUPZYAHONNHULX- (C1═CC═CC═C1)C1═CC═CC═C1)C1CCCCC1 CJBSCAABSA-N CN[C@@H](C)C(═O)N[C@H](C(═O)N1CCC[C@H]1C(═O)N[C@H](C(═O)OC)C UUPZYAHONNHULX- (C1═CC═CC═C1)C1═CC═CC═C1)C1CCCCC1 CJBSCAABSA-N CN[C@@H](C)C(═O)N[C@H](C(═O)N1CCC[C@H]1C1═NC(C(═O)C2═CC═CC LCQFGFLQFLFDST- (OC)═C2)═CS1)C1CCCCC1 RTFZILSDSA-N CN[C@@H](C)C(═O)N[C@H](C(═O)N1CCC[C@H]1C1═NC(C(═O)C2═CC═CC LCQFGFLQFLFDST- (OC)═C2)═CS1)C1CCCCC1 RTFZILSDSA-N CN[C@@H](C)C(═O)N[C@H](C(═O)N1CCC[C@H]1C1═NC(C(═O)C2═CC═CC LCQFGFLQFLFDST- (OC)═C2)═CS1)C1CCCCC1 RTFZILSDSA-N CN[C@@H](QC(═O)N[C@H](C(═O)N1C[C@@H](OC2═CC═CC═C2)C[C@H]1C(═O) GUOVHJVNYPRNQS- N[C@@H]1CCCC2═CC═CC═C21)C1CCCCC1 SHUILBLCSA-N CN[C@@H](C)C(═O)N[C@H](C(═O)N1C[C@H](OC2═CC═CC═C2)C[C@H]1C(═O) GUOVHJVNYPRNQS- N[C@@H]1CCCC2═CC═CC═C21)C1CCCCC1 XIKYZZKVSA-N CN[C@@H](C)C(═O)N[C@H](C(═O)N[C@H]1C[C@H]2CC[C@@H]1N(CCC1═CC═CC═C1) GBQXNBCXOOCMBG- C2)C1CCCCC1 CFYMNZCRSA-N CN[C@@H](C)C(═O)N[C@H](C(═O)N[C@H]1C[C@H]2CC[C@@H]1N(CCC1═CC═CC═C1) GBQXNBCXOOCMBG- C2)C1CCCCC1 CFYMNZCRSA-N CN[C@@H](C)C(═O)N[C@H](C(═O)N1CCC[C@H]1C1═NC(C2═CC═C(F) OXVDUVSHCWCOFU- C3═CC═CC═C23)═CS1)C1CCCCC1 ATANMQQVSA-N CN[C@@H](C)C(═O)N[C@HJ(C(═O)N1CCC[C@H]1C1═NC2═C(C3═CC═CC═C3)N═CC═C2 DAXYGNXUBMFNHC- S1)C1CCCCC1 XZOYJPPVSA-N CN[C@@H](C)C(═O)N[C@H](C(═O)N1CCC[C@H]1C1═CN═CC(C2═CC═C(F)C(C(═O) ORPIGORNDCHEIA- O)═C2)═C1)C1CCCCC1 HDBFHEOPSA-N CN[C@@H](C)C(═O)N[C@H](C(═O)N1CCC[C@H]1C1═CN═CC(N2C═CC3═C(C(═O)O)C FFGHOKFUXXWKFH- ═CC═C32)═C1)C(C)C OWSXEPHWSA-N CN[C@@H](C)C(═O)N[C@H](C(═O)N1CCC[C@H]1C(═O)NC1═C(C2═CC═CC═C2)N═NS1) WZRFLSDVFPIXOV- C1CCCCC1 LRQRDZAKSA-N CN[C@@H](C)C(═O)N[C@H](C(═O)N1CCC[C@H]1C(═O)NC1═C(C2═CC═CC═C2)N═NS1) WZRFLSDVFPIXOV- C1CCCCC1 LRQRDZAKSA-N CN[C@@H](C)C(═O)N[C@H](C(═O)N1CCC[C@H]1C(═O)NC1═C(C2═CC═CC═C2)N═NS1) WZRFLSDVFPIXOV- C1CCCCC1 LRQRDZAKSA-N CN[C@@H](OC(═O)N[C@H](C(═O)N1CCC[C@H]1C1═CN═CC(C(═O)C2═CC═C(F) PLYJYKAWZXEBFC- C═C2)═C1)C1CCCCC1 WDNCENIBSA-N NC1═CC═C2C(═O)N(C3CCC(═O)NC3═O)C(═O)C2═C1 IICWMVJMJVXCLY- UHFFFAOYSA-N CN[C@@H](C)C(═O)N[C@H]1CCO[C@H]2CC(C)(C)[C@@H](C(═O)N[C@@H]3CCC PBGOFGSVVXGJCA- C4═CC═CC═C43)N2C1═O KDJJVYBXSA-N O═C1CCC(N2C(═O)C3═CC═CC4═CC═CC(═C34)C2═O)C(═O)N1 BERVIROBWDIAQO- UHFFFAOYSA-N COC1═CC═C(OC2═CC═C(N(CC3═CC═CC═C3)C(═O)CC1)C═C2)C═C1 DPADEQNOMBTITM- UHFFFAOYSA-N CN1CCN(C2═CC═C(NC3CCC(═O)NC3═O)C═C2)CC1 GRQMMULSBXXEST- UHFFFAOYSA-N O═C1CCC(N2C(═O)OC3═CC═CC═C32)C(═O)N1 WCKFQKVNTHAOGC- UHFFFAOYSA-N NC1═CC═CC2═C1CN([C@H]1CCC(═O)NC1═O)C2═O GOTYRUGSSMKFNF- JTQLQIEISA-N COC(═O)C[C@H]1[C@12(C)C3═C(C)[C@H](C4═COC═C4)C[C@H]3O[C@@H]2 JZIQWNPPBKFOPT- [C@@H]2OC(═O)[C@]3(C)C═CC(═O)[C@@]1(C)[C@@H]23 LSYMHUITSA-N COC1═CC═CC2═C1C(═O)N(C1CCC(═O)NC1═O)C2 WQBYRVHGTFSBTA- UHFFFAOYSA-N O═C(CC1)NC(C(═O)NCC1═CC═CC═C1)C1═CC═C(C1)C(C1)═C1 IARWWDNCNPMRCK- UHFFFAOYSA-N O═C(CC1)NC(C(═O)NCC1═CC═CC═C1)C1═CC═C(C1)C═C1 OOWBZXBMBGHPDI- UHFFFAOYSA-N

Table 4 shows selections of the cell-penetrating peptide module, including but not limited to the sequences indicated by “cell-penetrating peptide sequence”, as shown in Table 4 below for details.

Cell-penetrating peptide sequence Cell-penetrating peptide sequence KKRRQRRRPPQ (SEQ ID NO: 19) akvkdepqrrsarlsakpappkpepkpkkapakk LGISYGRKKRRQRRRPPQ (SEQ ID NO: PLSSIFSRIGDP (SEQ ID NO: 413) 20) FITKALGISYGRKKRRQRRRPPQ (SEQ PSSSSSSRIGDP (SEQ ID NO: 414) ID NO: 21) FITKALGISYGRKKRR (SEQ ID NO: 22) vrlpppvrlpppvrlppp GRKKRRQRRR (SEQ ID NO: 23) VELPPPVELPPPVELPPP (SEQ ID NO: 415) RKKRRQRRR (SEQ ID NO: 24) ALWMTLLKKVLKAAAKAALNAVLVGANA (SEQ ID NO: 416) RKKRRQRR (SEQ ID NO: 25) ALWKTLLKKVLKA (SEQ ID NO: 417) RKKRRQR (SEQ ID NO: 26) ALWKTLLKKVLKAPKKKRKV (SEQ ID NO: 418) KKRRQRRR (SEQ ID NO: 27) PKKKRKVALWKTLLKKVLKA (SEQ ID NO: 419) KRRQRRR (SEQ ID NO: 28) VKRKKKPALWKTLLKKVLKA (SEQ ID NO: 420) rkkrrqrrr RQARRNRRRALWKTLLKKVLKA (SEQ ID NO: 421) RRRQRRKKR (SEQ ID NO: 29) RQARRNRRRC (SEQ ID NO: 422) rrrqrrkkr GRKKRRQRRRPPQC (SEQ ID NO: 423) AKKRRQRRR (SEQ ID NO: 30) EEEAAGRKRKKRT (SEQ ID NO: 424) RAKRRQRRR (SEQ ID NO: 31) EEE RKARRQRRR (SEQ ID NO: 32) EEEAA (SEQ ID NO: 425) RKKARQRRR (SEQ ID NO: 33) EEEAAKKK (SEQ ID NO: 426) RKKRAQRRR (SEQ ID NO: 34) GRKRKKRT (SEQ ID NO: 427) RKKRRARRR (SEQ ID NO: 35) FFFAAGRKRKKRT (SEQ ID NO: 428) RKKRRQARR (SEQ ID NO: 36) NNNAAGRKRKKRT (SEQ ID NO: 429) RKKRRQRAR (SEQ ID NO: 37) YYYAAGRKRKKRT (SEQ ID NO: 430) RKKRRQRRA (SEQ ID NO: 38) MVTVLFRRLRIRRACGPPRVRV (SEQ ID NO: 431) GRKKRRQRRPPQC (SEQ ID NO: 39) RQIKIWFQNRRMKWKK (SEQ ID NO: 432) GRKKRRQRPPQC (SEQ ID NO: 40) AGYLLGKINLKALAALAKKIL (SEQ ID NO: 433) GRKKRRQPPQC (SEQ ID NO: 41) VQRKRQKLMP (SEQ ID NO: 434) GRKKRRQRRRC (SEQ ID NO: 42) SKKKKTKV (SEQ ID NO: 435) GRKKRRQRARPPQC (SEQ ID NO: 43) GRKRKKRT (SEQ ID NO: 436) GRKKRRQARAPPQC (SEQ ID NO: 44) GKKKKRKREKL (SEQ ID NO: 437) TRQARRNRRRRWRERQR (SEQ ID NO: 45) PKKKRKV (SEQ ID NO: 438) RRRR (SEQ ID NO: 46) ERKKRRRE (SEQ ID NO: 439) RRRRR (SEQ ID NO: 47) FKKFRKF (SEQ ID NO: 440) RRRRRR (SEQ ID NO: 48) LGTYTQDFNKFHTFPQTAIGVGAP (SEQ ID NO: 441) RRRRRRR (SEQ ID NO: 49) LGTYTQDFNKFHTFPQTAIGVGAP (SEQ ID NO: 442) RRRRRRRR (SEQ ID NO: 2) YTQDFNKFHTFPQTAIGVGAP (SEQ ID NO: 443) RRRRRRRRR (SEQ ID NO: 50) DFNKFHTFPQTAIGVGAP (SEQ ID NO: 444) RRRRRRRRRRR (SEQ ID NO: 51) KFHTFPQTAIGVGAP (SEQ ID NO: 445) RRRRRRRRRRRR (SEQ ID NO: 52) TFPQTAIGVGAP (SEQ ID NO: 446) RRRRRRRRRRRRRRRR (SEQ ID NO: 53) GYGRKKRRQRRRG (SEQ ID NO: 447) rrrrr GYGRKKRRQRRRG (SEQ ID NO: 448) rrrrrr GYGRKKRRQRRRG (SEQ ID NO: 449) rrrrrrr RQIKIWFQNRRMKWKK (SEQ ID NO: 450) rrrrrrrr RQIKIWFQNRRMKWKK (SEQ ID NO: 450) rrrrrrrrr RQIKIWFQNRRMKWKK (SEQ ID NO: 450) GWTLNSAGYLLGKINLKALAALAKKIL FLGKKFKKYFLQLLK (SEQ ID NO: 451) (SEQ ID NO: 54) GWTLNSAGYLLGKINLKALAALAKKLL FLIFIR VICIVIAKLKANLMCKT (SEQ ID NO: 452) (SEQ ID NO: 55) GWTLNSAGYLLGKFLPLILRKIVTAL KKAAQIRSQVMTHLRVI (SEQ ID NO: 453) (SEQ ID NO: 56) GWTLNPAGYLLGKINLKALAALAKKIL YIVLRRRRKRVNTKRS (SEQ ID NO: 454) (SEQ ID NO: 57) GWTLNPPGYLLGKINLKALAALAKKIL RRKLSQQKEKK (SEQ ID NO: 455) (SEQ ID NO: 58) LNSAGYLLGKINLKALAALAKKIL (SEQ VQAILRRNWNQYKIQ (SEQ ID NO: 456) ID NO: 59) LLGKINLKALAALAKKIL (SEQ ID NO: KTVLLRKLLKLLVRKI (SEQ ID NO: 457) 60) GWTLNSAGYLLGKLKALAALAKKIL LLKKRKVVRLIKFLLK (SEQ ID NO: 458) (SEQ ID NO: 61) AGYLLGKINLKALAALAKKIL (SEQ ID KLPCRSNTFLNIFRRKKPG (SEQ ID NO: 459) NO: 62) GWTLNSKINLKALAALAKKIL (SEQ ID KKICTRKPRFMSAWAQ (SEQ ID NO: 460) NO: 63) LNSAGYLLGKLKALAALAKIL (SEQ ID RQIKIWFQNRRMKWKK (SEQ ID NO: 461) NO: 64) LNSAGYLLGKALAALAKKIL (SEQ ID RGGRLSYSRRRFSTSTGR (SEQ ID NO: 462) NO: 65) AGYLLGKLKALAALAKKIL (SEQ ID rggrlsysrrrfststgr NO: 66) LNSAGYLLGKLKALAALAK (SEQ ID RRLSYSRRRF (SEQ ID NO: 463) NO: 67) GWTLNSAGYLLGKINLKAPAALAKKIL rrlsysrrrf (SEQ ID NO: 68) GWTLNSAGYLLGPHAVGNHRSFSDKN RGGRLAYLRRRWAVLGR (SEQ ID NO: 464) GLTS (SEQ ID NO: 69) INLKALAALAKKIL (SEQ ID NO: 70) RQIKIWFQNRRMKWKK (SEQ ID NO: 465) KLALKLALKALKAALKLA (SEQ ID NO: MANLGYWLLALFVTMWTDVGLCKKRPKP (SEQ ID NO: 71) 466) KLALKLALKAWKAALKLA (SEQ ID MANLGCWMLVLFVATWSDLGLCKKRPKP (SEQ ID NO: NO: 72) 467) KLALKAALKAWKAAAKLA (SEQ ID MVKSKIGSWILVLFVAMWSDVGLCKKRPKP (SEQ ID NO: NO: 73) 468) KLALKAAAKAWKAAAKAA (SEQ ID LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTESC (SEQ NO: 74) ID NO: 469) KITLKLAIKAWKLALKAA (SEQ ID NO: RQIKIWFQNRRMKWKK (SEQ ID NO: 470) 75) KIAAKSIAKIWKSILKIA (SEQ ID NO: RVIRVWFQNKRCKDKK (SEQ ID NO: 471) 76) KALAKALAKLWKALAKAA (SEQ ID GIGKFLHSAKKWGKAFVGQIMNC (SEQ ID NO: 472) NO: 77) KLALKLALKWAKLALKAA (SEQ ID TRSSRAGLQWPVGRVHRLLRKGGC (SEQ ID NO: 473) NO: 78) KLLAKAAKKWLLLALKAA (SEQ ID YGRKKRRQRRR (SEQ ID NO: 1) NO: 79) KLLAKAALKWLLKALKAA (SEQ ID RHIKIWFQNRRMKWKK (SEQ ID NO: 474) NO: 80) KALKKLLAKWLAAAKALL (SEQ ID RKKRRQRRR (SEQ ID NO: 475) NO: 81) KLAAALLKKWKKLAAALL (SEQ ID RQIKIWFQNRRMKWKK (SEQ ID NO: 476) NO: 82) KALAALLKKWAKLLAALK (SEQ ID SKRTRQTYTRYQTLELEKEFHFNRYITRRRRIDIANALSLSE NO: 83) RQIKIWFQNRRMKSKKDR (SEQ ID NO: 477) KALAALLKKLAKLLAALK (SEQ ID NO: EKRPRTAFSSEQLARLKREFNENRYLTTERRRQQLSSELGL 84) NEAQIKIWFQNKRAKIKKST (SEQ ID NO: 478) KLALKLALKALKAALK (SEQ ID NO: 85) GRRRRRRRRRPPQ (SEQ ID NO: 479) KLALKALKAALKLA (SEQ ID NO: 86) GALFLGFLGAAGSTMGAWSQPKKKRKV (SEQ ID NO: 480) KLALKLALKALKAA (SEQ ID NO: 87) GALFLAFLAAALSLMGLWSQPKKKRRV (SEQ ID NO: 481) KLGLKLGLKGLKGGLKLG (SEQ ID NO: 88) MLLLTRRRST (SEQ ID NO: 482) KLALKLALKALQAALQLA (SEQ ID NO: 89) CGNKRTRGC (SEQ ID NO: 483) KLALQLALQALQAALQLA (SEQ ID NO: 90) TSPLNIHNGQKL (SEQ ID NO: 484) QLALQLALQALQAALQLA (SEQ ID NO: 91) GLRKRLRKFRNKIKEK (SEQ ID NO: 485) ELALELALEALEAALELA (SEQ ID NO: 92) GLLEALAELLEGLRKRLRKFRNKIKEK (SEQ ID NO: 486) LKTLATALTKLAKTLTTL (SEQ ID NO: 93) CVQWSLLRGYQPC (SEQ ID NO: 487) LLKTTALLKTTALLKTTA (SEQ ID NO: 94) VRLPPP (SEQ ID NO: 488) LKTLTETLKELTKTLTEL (SEQ ID NO: 95) VRLPPPVRLPPP (SEQ ID NO: 489) LLKTTELLKTTELLKTTE (SEQ ID NO: 96) VRLPPPVRLPPPVRLPPP (SEQ ID NO: 490) RQIKIWFQNRRMKWKK (SEQ ID NO: 97) VHLPPP (SEQ ID NO: 491) klalklalkalkaalkla VHLPPPVHLPPP (SEQ ID NO: 492) KALKLKLALALLAKLKLA (SEQ ID NO: 98) VHLPPPVHLPPPVHLPPP (SEQ ID NO: 493) RQIKIWFQNRRMKWKK (SEQ ID NO: 99) VKLPPP (SEQ ID NO: 494) KKWKMRRNQFWIKIQR (SEQ ID NO: 100) VKLPPPVKLPPP (SEQ ID NO: 495) rqikiwfqnrrmkwkk VKLPPPVKLPPPVKLPPP (SEQ ID NO: 496) RQIKIWFPNRRMKWKK (SEQ ID NO: 101) RQIKIWFQNRRMKWKK (SEQ ID NO: 497) RQPKIWFPNRRKPWKK (SEQ ID NO: 102) RQIKIFFQNRRMKWKK (SEQ ID NO: 498) RQIKIWFQNRRMKWKK (SEQ ID NO: 103) ASMWERVKSIIKSSLAAASNI (SEQ ID NO: 499) RQIKIWFQNRRMKWK (SEQ ID NO: 3) ASMWERVKSIIKSSLAAASNI (SEQ ID NO: 500) RQIKIWFQNRRMKW (SEQ ID NO: 104) DPKGDPKGVTVTVTVTVTGKGDPKPD (SEQ ID NO: 501) RQIKIWFQNRRMK (SEQ ID NO: 105) CSIPPEVKFNPFVYLI (SEQ ID NO: 502) RQIKIWFQNRRM (SEQ ID NO: 106) csippevkfnpfvyli RQIKIWFQNRR (SEQ ID NO: 107) PFVYLI (SEQ ID NO: 503) RQIKIWFQNR (SEQ ID NO: 108) NKPILVFY (SEQ ID NO: 504) RQIKIWFQN (SEQ ID NO: 109) YKQCHKKGGKKGSG (SEQ ID NO: 505) RQIKIWFQ (SEQ ID NO: 110) YKQCHKKGGXKKGSG (SEQ ID NO: 506) RQIKIW (SEQ ID NO: 111) GSGKKGGKKHCQKY (SEQ ID NO: 507) QIKIWFQNRRMKWKK (SEQ ID NO: 112) GSGKKGGKKICQKY (SEQ ID NO: 508) IKIWFQNRRMKWKK (SEQ ID NO: 113) YTAIAWVKAFIRKLRK (SEQ ID NO: 509) KIWFQNRRMKWKK (SEQ ID NO: 114) IAWVKAFIRKLRKGPLG (SEQ ID NO: 510) IWFQNRRMKWKK (SEQ ID NO: 115) LIRLWSHLIHIWFQNRRLKWKKK (SEQ ID NO: 511) WFQNRRMKWKK (SEQ ID NO: 116) KKKKKKGGFLGFWRGENGRKTRSAYERMCILKGK (SEQ ID NO: 512) FQNRRMKWKK (SEQ ID NO: 117) RLSGMNEVLSFRWL (SEQ ID NO: 513) QNRRMKWKK (SEQ ID NO: 118) GPFHFYQFLFPPV (SEQ ID NO: 514) NRRMKWKK (SEQ ID NO: 119) GSPWGLQHHPPRT (SEQ ID NO: 515) RRMKWKK (SEQ ID NO: 120) AAVALLPAVLLALLAP (SEQ ID NO: 516) RMKWKK (SEQ ID NO: 121) AAVALLPAVLLALLAPEILLPNNYNAYESYKYPGMFIALSK (SEQ ID NO: 517) AQIKIWFQNRRMKWKK (SEQ ID NO: 122) AAVALLPAVLLALLAPVQRKRQKLMP (SEQ ID NO: 518) RAIKIWFQNRRMKWKK (SEQ ID NO: 123) WEAKLAKALAKALAKHLAKALAKALKACEA (SEQ ID NO: 519) RQAKIWFQNRRMKWKK (SEQ ID NO: 124) MGLGLHLLVLAAALQGAWSQPKKKRKV (SEQ ID NO: 520) RQIAIWFQNRRMKWKK (SEQ ID NO: 125) MGLGLHLLVLAAALQGAKKKRKV (SEQ ID NO: 521) RQIKAWFQNRRMKWKK (SEQ ID NO: 126) WEAALAEALAEALAEHLAEALAEALEALAA (SEQ ID NO: 522) RQIKIAFQNRRMKWKK (SEQ ID NO: 127) GLFEALLELLESLWELLLEA (SEQ ID NO: 523) RQIKIWAQNRRMKWKK (SEQ ID NO: 128) GLFKALLKLLKSLWKLLLKA (SEQ ID NO: 524) RQIKIWFANRRMKWKK (SEQ ID NO: 129) GLFRALLRLLRSLWRLLLRA (SEQ ID NO: 525) RQIKIWFQARRMKWKK (SEQ ID NO: 130) CGAYDLRRRERQSRLRRRERQSR (SEQ ID NO: 526) RQIKIWFQNARMKWKK (SEQ ID NO: 131) RKKRRRESRKKRRRESC (SEQ ID NO: 527) RQIKIWFQNRAMKWKK (SEQ ID NO: 132) CVKRGLKLRHVRPRVTRDV (SEQ ID NO: 528) RQIKIWFQNRRAKWKK (SEQ ID NO: 133) CRQIKIWFQNRRMKWKK (SEQ ID NO: 529) RQIKIWFQNRRMAWKK (SEQ ID NO: 134) YARAAARQARA (SEQ ID NO: 530) RQIKIWFQNRRMKAKK (SEQ ID NO: 135) PPKKSAQCLRYKKPE (SEQ ID NO: 531) RQIKIWFQNRRMKWAK (SEQ ID NO: 136) DPVDTPNPTRRKPGK (SEQ ID NO: 532) RQIKIWFQNRRMKWKA (SEQ ID NO: 137) KRVSRNKSEKKRR (SEQ ID NO: 533) CRQIKIWFPNRRMKWKKC (SEQ ID NO: GRRHHCRSKAKRSRHH (SEQ ID NO: 534) 138) RQIKIWFPNRRMKWKK (SEQ ID NO: 139) SARHHCRSKAKRSRHH (SEQ ID NO: 535) RQIKIWFQNRRMKWKK (SEQ ID NO: 140) SRAHHCRSKAKRSRHH (SEQ ID NO: 536) RQIKIFFQNRRMKFKK (SEQ ID NO: 141) SRRAHCRSKAKRSRHH (SEQ ID NO: 537) RQIRIWFQNRRMRWRR (SEQ ID NO: 142) SRRHACRSKAKRSRHH (SEQ ID NO: 538) RRRRRRRW (SEQ ID NO: 143) SRRHHARSKAKRSRHH (SEQ ID NO: 539) GRKKRRQRRRPWQ (SEQ ID NO: 144) SRRHHCRAKAKRSRHH (SEQ ID NO: 540) GRKKRRQRRRPWQ (SEQ ID NO: 145) SRRHHCRSAAKRSRHH (SEQ ID NO: 541) RQIRIWFQNRRMRWRR (SEQ ID NO: 146) SRRHHCRSKAARSRHH (SEQ ID NO: 542) RRWRRWWRRWWRRWRR (SEQ ID NO: 147) SRRHHCRSKAKASRHH (SEQ ID NO: 543) RQIKIWFQNMRRKWKK (SEQ ID NO: 148) SRRHHCRSKAKRARHH (SEQ ID NO: 544) KMDCRWRWKCCKK (SEQ ID NO: 149) SRRHHCRSKAKRSAHH (SEQ ID NO: 545) MDCRWRWKCCKK (SEQ ID NO: 150) RRHHCRSKAKRSR (SEQ ID NO: 546) DCRWRWKCCKK (SEQ ID NO: 151) GRKGKHKRKKLP (SEQ ID NO: 547) CRWRWKCCKK (SEQ ID NO: 152) GKKKKKKKKK (SEQ ID NO: 548) RWRWKCCKK (SEQ ID NO: 153) GKRVAKRKLIEQNRERRR (SEQ ID NO: 549) KMDCRWRWKCKK (SEQ ID NO: 154) GRKLKKKKNEKEDKRPRT (SEQ ID NO: 550) KMDCRWRWKKK (SEQ ID NO: 155) GKKTNLFSALIKKKKTA (SEQ ID NO: 551) KMDRWRWKKK (SEQ ID NO: 156) GRRERNKMAAAKCRNRRR (SEQ ID NO: 552) KDCRWRWKCCKK (SEQ ID NO: 157) GKRARNTEAARRSRARKL (SEQ ID NO: 553) KCRWRWKCCKK (SEQ ID NO: 158) GRRRRATAKYRTAH (SEQ ID NO: 554) KRWRWKCCKK (SEQ ID NO: 159) GKRRRRATAKYRSAH (SEQ ID NO: 555) MDCRWRWKXCKK (SEQ ID NO: 160) GRRRRKRLSHRT (SEQ ID NO: 556) DCRWRWKXCKK (SEQ ID NO: 161) GRRRRRERNK (SEQ ID NO: 557) DCRWRWKCXKK (SEQ ID NO: 162) GKHRHERGHHRDRRER (SEQ ID NO: 558) CRWRWKXCKK (SEQ ID NO: 163) GKKKRKLSNRESAKRSR (SEQ ID NO: 559) CRWRWKCXKK (SEQ ID NO: 164) MITYRDLISH (SEQ ID NO: 560) RWRWKXCKK (SEQ ID NO: 165) MITYRDLIS (SEQ ID NO: 561) MDCRWRWKXXKK (SEQ ID NO: 166) MITYRDLI (SEQ ID NO: 562) DCRWRWKXXKK (SEQ ID NO: 167) IIYRDLISH (SEQ ID NO: 563) CRWRWKXXKK (SEQ ID NO: 168) MITYRDL (SEQ ID NO: 564) RWRWKXXKK (SEQ ID NO: 169) MITYRD (SEQ ID NO: 565) CRWRWKCSKK (SEQ ID NO: 170) IYRDLISH (SEQ ID NO: 566) SRWRWKCCKK (SEQ ID NO: 171) AITYRDLIS (SEQ ID NO: 567) SRWRWKCSKK (SEQ ID NO: 172) MAIYRDLIS (SEQ ID NO: 568) SRWRWKSCKK (SEQ ID NO: 173) MIAYRDLIS (SEQ ID NO: 569) CRWRWKSSKK (SEQ ID NO: 174) MIIARDLIS (SEQ ID NO: 570) SRWRWKSSKK (SEQ ID NO: 175) MITYADLIS (SEQ ID NO: 571) CRFRWKCCKK (SEQ ID NO: 176) MITYRALIS (SEQ ID NO: 572) CRWRFKCCKK (SEQ ID NO: 177) MITYRDAIS (SEQ ID NO: 573) CRFRFKCCKK (SEQ ID NO: 178) MITYRDLAS (SEQ ID NO: 574) crwrwkcckk MITYRDLIA (SEQ ID NO: 575) KCCKWRWRCK (SEQ ID NO: 179) MITYRDLISKK (SEQ ID NO: 576) kcckwrwrck MITYRDKKSH (SEQ ID NO: 577) CrWRWKCCKK MIIFRDLISH (SEQ ID NO: 578) CRwRWKCCKK MIISRDLISH (SEQ ID NO: 579) CRWrWKCCKK QIISRDLISH (SEQ ID NO: 580) CRWRwKCCKK CIISRDLISH (SEQ ID NO: 581) CrwrwKCCKK MITYRALISHKK (SEQ ID NO: 582) CRWRWKCGCKK (SEQ ID NO: 180) MITYRIAASHKK (SEQ ID NO: 583) KCGCRWRWKCGCKK (SEQ ID NO: 181) MIIRRDLISE (SEQ ID NO: 584) CRWRWKCG (SEQ ID NO: 182) MITYRAEISH (SEQ ID NO: 585) KMDXRWRWKCCKK (SEQ ID NO: 183) MIIYARRAEE (SEQ ID NO: 586) KMDXRWRWKXCKK (SEQ ID NO: 184) MIIFRIAASHKK (SEQ ID NO: 587) KMDXRWRWKXXKK (SEQ ID NO: 185) MIIFRALISHKK (SEQ ID NO: 588) KMDXRWRWKCXKK (SEQ ID NO: 186) MIIFRAAASHKK (SEQ ID NO: 589) MDCRWRWKCXKK (SEQ ID NO: 187) FIIFRIAASHKK (SEQ ID NO: 590) KMDCRWRWKCSKK (SEQ ID NO: 188) LIIFRIAASHKK (SEQ ID NO: 591) KMDCRWRWKSCKK (SEQ ID NO: 189) WIIFRIAASHKK (SEQ ID NO: 592) KMDSRWRWKCCKK (SEQ ID NO: 190) WIIFRAAASHKK (SEQ ID NO: 593) KMDCRWRWKSSKK (SEQ ID NO: 191) WIIFRALISHKK (SEQ ID NO: 594) KMDSRWRWKSSKK (SEQ ID NO: 192) MIIFRIAAYHKK (SEQ ID NO: 595) KMDSRWRWKSCKK (SEQ ID NO: 193) WIIFRIAAYHKK (SEQ ID NO: 596) KMDSRWRWKCSKK (SEQ ID NO: 194) MIIFRIAATHKK (SEQ ID NO: 597) KMDCRWRPKCCKK (SEQ ID NO: 195) WIIFRIAATHKK (SEQ ID NO: 598) KMDCRPRPKCCKK (SEQ ID NO: 196) MIIFKIAASHKK (SEQ ID NO: 599) KMDXRPRPKCCKK (SEQ ID NO: 197) WIIFKIAASHKK (SEQ ID NO: 600) KMDXRPRPKXCKK (SEQ ID NO: 198) MIIFAIAASHKK (SEQ ID NO: 601) KMDXRPRPKCXKK (SEQ ID NO: 199) LIIFRILISHKK (SEQ ID NO: 602) KMDCRPRPKXCKK (SEQ ID NO: 200) MIIFRILISHKK (SEQ ID NO: 603) KMDCRPRPKCXKK (SEQ ID NO: 201) LIIFRILISHRR (SEQ ID NO: 604) RQIKIWFQNRRMKWKK (SEQ ID NO: 202) LIIFRILISHHH (SEQ ID NO: 605) rkkrrqrrr LIIFRILISHK (SEQ ID NO: 606) rrrqrrkkr LIIFRILISHR (SEQ ID NO: 607) rrrrrrrr LIIFRILISH (SEQ ID NO: 608) RKKRRRESRKKRRRES (SEQ ID NO: 203) LIIFAIAASHKK (SEQ ID NO: 609) GRPRESGKKRKRKRLKP (SEQ ID NO: 204) LIIFAILISHKK (SEQ ID NO: 610) GKRKKKGKLGKKRDP (SEQ ID NO: 205) RILQQLLFIHFRIGCRHSRI (SEQ ID NO: 611) GKRKKKGKLGKKRPRSR (SEQ ID NO: 206) RILQQLLFIHFRIGCRH (SEQ ID NO: 612) RKKRRRESRRARRSPRHL (SEQ ID NO: RILQQLLFIHFRIGC (SEQ ID NO: 613) 207) SRRARRSPRESGKKRKRKR (SEQ ID RIFIHFRIGC (SEQ ID NO: 614) NO: 208) VKRGLKLRHVRPRVTRMDV (SEQ ID RIFIRIGC (SEQ ID NO: 615) NO: 209) SRRARRSPRHLGSG (SEQ ID NO: 210) RILQQLLFIHF (SEQ ID NO: 616) LRRERQSRLRRERQSR (SEQ ID NO: RIFIGC (SEQ ID NO: 617) 211) GAYDLRRRERQSRLRRRERQSR (SEQ FIRIGC (SEQ ID NO: 618) ID NO: 212) GRKKRRQRRRPPQ (SEQ ID NO: 213) DTWAGVEAIIRILQQLLFIHFR (SEQ ID NO: 619) VPMLK (SEQ ID NO: 214) IGCRH (SEQ ID NO: 620) VPTLK (SEQ ID NO: 215) RQIKIWFQNRRMKWKK (SEQ ID NO: 621) VPALR (SEQ ID NO: 216) GYGRKKRRGRRRTHRLPRRRRRR (SEQ ID NO: 622) VSALK (SEQ ID NO: 217) KRIIQRILSRNS (SEQ ID NO: 623) PMLKE (SEQ ID NO: 218) KRIHPRLTRSIR (SEQ ID NO: 624) VPALK (SEQ ID NO: 219) PPRLRKRRQLNM (SEQ ID NO: 625) VSLKK (SEQ ID NO: 220) PIRRRKKLRRLK (SEQ ID NO: 626) VSGKK (SEQ ID NO: 221) RRQRRTSKLMKR (SEQ ID NO: 627) KLPVM (SEQ ID NO: 222) MHKRPTTPSRKM (SEQ ID NO: 628) IPMIK (SEQ ID NO: 223) RQRSRRRPLNIR (SEQ ID NO: 629) KLGVM (SEQ ID NO: 224) RIRMIQNLIKKT (SEQ ID NO: 630) KLPVT (SEQ ID NO: 225) SRRKRQRSNMRI (SEQ ID NO: 631) VPMIK (SEQ ID NO: 226) QRIRKSKISRTL (SEQ ID NO: 632) IPALK (SEQ ID NO: 627) PSKRLLHNNLRR (SEQ ID NO: 633) IPMLK (SEQ ID NO: 228) HRHIRRQSLIML (SEQ ID NO: 634) VPTLQ (SEQ ID NO: 229) PQNRLQIRRHSK (SEQ ID NO: 635) QLPVM (SEQ ID NO: 230) PPHNRIQRRLNM (SEQ ID NO: 636) ELPVM (SEQ ID NO: 231) SMLKRNHSTSNR (SEQ ID NO: 637) VPTLE (SEQ ID NO: 232) GSRHPSLIIPRQ (SEQ ID NO: 638) vptlk SPMQKTMNLPPM (SEQ ID NO: 639) RRRRRRRR (SEQ ID NO: 2) NKRILIRIMTRP (SEQ ID NO: 640) AYRIKPTFRRLKWKYKGKFW (SEQ ID HGWZIHGLLHRA (SEQ ID NO: 641) NO: 233) HARIKPTFRRLKWKYKGKFW (SEQ ID AVPAKKRZKSV (SEQ ID NO: 642) NO: 234) HYRIKPTARRLKWKYKGKFW (SEQ ID PNTRVRPDVSF (SEQ ID NO: 643) NO: 235) HYRIKPTFRRLAWKYKGKFW (SEQ ID LTRNYEAWVPTP (SEQ ID NO: 644) NO: 236) HYRIKPTFRRLKWKYKGKFA (SEQ ID SAETVESCLAKSH (SEQ ID NO: 645) NO: 237) VNADIKATTVFGGKYVSLTTP (SEQ ID YSHIATLPFTPT (SEQ ID NO: 646) NO: 238) GKYVSLTTPKNPTKRRITPKDV (SEQ ID SYIQRTPSTTLP (SEQ ID NO: 647) NO: 239) TKRRITPKDVIDVRSVTTEINT (SEQ ID AVPAENALNNPF (SEQ ID NO: 648) NO: 240) RSVTTEINTLFQTLTSIAEKVDP (SEQ ID SFHQFARATLAS (SEQ ID NO: 649) NO: 241) AEKVDPVKLNLTLSAAAEALTGLGDK QSPTDFTFPNPL (SEQ ID NO: 650) (SEQ ID NO: 242) GLGDKFGESIVNANTVLDDLNSRMPQS HFAAWGGWSLVH (SEQ ID NO: 651) RHDIQQL (SEQ ID NO: 243) GDVYADAAPDLFDFLDSSVTTARTINA HIQLSPFSQSWR (SEQ ID NO: 652) (SEQ ID NO: 244) ARTINAQQAELDSALLAAAGFGNTTAD LTMPSDLQPVLW (SEQ ID NO: 653) VFDRG (SEQ ID NO: 245) ADVFDRGGPYLQRGVADLVPTATLLDT FQPYDHPAEVSY (SEQ ID NO: 654) YSP (SEQ ID NO: 246) LDTYSPELFCTIRNFYDADRPDRGAAA FDPFFWKYSPRD (SEQ ID NO: 655) (SEQ ID NO: 247) TKRRITPKDVIDVRSVTTEINT (SEQ ID FAPWDTASFMLG (SEQ ID NO: 656) NO: 248) TKRRITPDDVIDVRSVTTEINT (SEQ ID FTYKNFFWLPEL (SEQ ID NO: 657) NO: 249) TKRRITPKKVIDVRSVTTEINT (SEQ ID SATGAPWKMWVR (SEQ ID NO: 658) NO: 250) TKRRITPKDVIDVRSVTTKINT (SEQ ID SLGWMLPFSPPF (SEQ ID NO: 659) NO: 251) TKRRITPKDVIDV (SEQ ID NO: 252) SHAFTWPTYLQL (SEQ ID NO: 660) TKRRITPKDVIDVESVTTEINT (SEQ ID SHNWLPLWPLRP (SEQ ID NO: 661) NO: 253) TARRITPKDVIDVRSVTTEINT (SEQ ID SWLPYPWHVPSS (SEQ ID NO: 662) NO: 254) TKAARITPKDVIDVRSVTTEINT (SEQ ID SWWTPWHVHSES (SEQ ID NO: 663) NO: 255) HHHHHHTKRRITPKDVIDVRSVTTEINT SWAQHLSLPPVL (SEQ ID NO: 664) (SEQ ID NO: 256) KLWMRWYSPTTRRYG (SEQ ID NO: 257) SSSIFPPWLSFF (SEQ ID NO: 665) DSLKSYWYLQKFSWR (SEQ ID NO: 258) LNVPPSWFLSQR (SEQ ID NO: 666) RTLVNEYKNTLKFSK (SEQ ID NO: 259) LDITPFLSLTLP (SEQ ID NO: 667) IPSRWKDQFWKRWHY (SEQ ID NO: 260) LPHPVLHMGPLR (SEQ ID NO: 668) GYGNCRHFKQKPRRD (SEQ ID NO: 261) VSKQPYYMWNGN (SEQ ID NO: 669) KNAWKHSSCHHRHQI (SEQ ID NO: 262) NYTTYKSHFQDR (SEQ ID NO: 670) RVREWWYTITLKQES (SEQ ID NO: 263) AIPNNQLGFPFK (SEQ ID NO: 671) QQHLLIAINGYPRYN (SEQ ID NO: 264) NIENSTLATPLS (SEQ ID NO: 672) WKCRRQCFRVLHHWN (SEQ ID NO: 265) YPYDANHTRSPT (SEQ ID NO: 673) RLWMRWYSPTTRRYG (SEQ ID NO: 266) DPATNPGPHFPR (SEQ ID NO: 674) KLWMRWYSATTRRYG (SEQ ID NO: 267) TLPSPLALLTVH (SEQ ID NO: 675) KLWMRWYSPWTRRYG (SEQ ID NO: 268) HPGSPFPPEHRP (SEQ ID NO: 676) RLWMRWYSPWTRRYG (SEQ ID NO: 269) TSHTDAPPARSP (SEQ ID NO: 677) RLWMRWYSPWTRRWG (SEQ ID NO: 270) MTPSSLSTLPWP (SEQ ID NO: 678) ALWMRWYSPTTRRYG (SEQ ID NO: 271) VLGQSGYLMPMR (SEQ ID NO: 679) RAWMRWYSPTTRRYG (SEQ ID NO: 272) QPIIITSPYLPS (SEQ ID NO: 680) RLAMRWYSPTTRRYG (SEQ ID NO: 273) TPKTMTQTYDFS (SEQ ID NO: 681) RLWARWYSPTTRRYG (SEQ ID NO: 274) NSGTMQSASRAT (SEQ ID NO: 682) RLWMAWYSPTTRRYG (SEQ ID NO: 275) QAASRVENYMHR (SEQ ID NO: 683) RLWMRAYSPTTRRYG (SEQ ID NO: 276) HQHKPPPLTNNW (SEQ ID NO: 684) RLWMRWASPTTRRYG (SEQ ID NO: 277) SNPWDSLLSVST (SEQ ID NO: 685) RLWMRWYAPTTRRYG (SEQ ID NO: 278) KTIEAHPPYYAS (SEQ ID NO: 686) RLWMRWYSPATRRYG (SEQ ID NO: 279) EPDNWSLDFPRR (SEQ ID NO: 687) RLWMRWYSPTARRYG (SEQ ID NO: 280) HQHKPPPLTNNW (SEQ ID NO: 688) RLWMRWYSPTTARYG (SEQ ID NO: 281) GLWRALWRLLRSLWRLLWKA (SEQ ID NO: 689) RLWMRWYSPTTRAYG (SEQ ID NO: 282)  GLWRALWRALWRSLWKLKRKV (SEQ ID NO: 690) RLWMRWYSPTTRRAG (SEQ ID NO: 283)  GLWRALWRALRSLWKLKRKV (SEQ ID NO: 691) RLWMRWYSPTTRRYA (SEQ ID NO: 284) GLWRALWRGLRSLWKLKRKV (SEQ ID NO: 692) RLLMRLYSPTTRRYG (SEQ ID NO: 285) GLWRALWRGLRSLWKKKRKV (SEQ ID NO: 693) RLFMRFYSPTTRRYG (SEQ ID NO: 286) GLWRALWRALWRSLWKLKWKV (SEQ ID NO: 694) RLIMRIYSPTTRRYG (SEQ ID NO: 287) GLWRALWRALWRSLWKSKRKV (SEQ ID NO: 695) RLVMRVYSPTTRRYG (SEQ ID NO: 288) GLWRALWRALWRSLWKKKRKV (SEQ ID NO: 696) RLYMRYYSPTTRRYG (SEQ ID NO: 289) GLWRALWRALWRSLWKLKRKV (SEQ ID NO: 697) YGRKKKRRQRRR (SEQ ID NO: 290) GLWRALWRLLRSLWRLLWSQPKKKRKV (SEQ ID NO: 698) LLIILRRRIRKQAHAHSK (SEQ ID NO: YARAARRAARR (SEQ ID NO: 699) 291) ALIILRRRIRKQAHAHSK (SEQ ID NO: PARAARRAARR (SEQ ID NO: 700) 292) LAIILRRRIRKQAHAHSK (SEQ ID NO: YPRAARRAARR (SEQ ID NO: 701) 293) LLAILRRRIRKQAHAHSK (SEQ ID NO: YRRAARRAARA (SEQ ID NO: 702) 294) LLIALRRRIRKQAHAHSK (SEQ ID NO: YGRAARRAARR (SEQ ID NO: 703) 295) LLIIARRRIRKQAHAHSK (SEQ ID NO: YAREARRAARR (SEQ ID NO: 704) 296) LLIILARRIRKQAHAHSK (SEQ ID NO: YEREARRAARR (SEQ ID NO: 705) 297) LLIILRARIRKQAHAHSK (SEQ ID NO: YKRAARRAARR (SEQ ID NO: 706) 298) LLIILRRAIRKQAHAHSK (SEQ ID NO: YARKARRAARR (SEQ ID NO: 707) 299) LLIILRRRARKQAHAHSK (SEQ ID NO: YKRKARRAARR (SEQ ID NO: 708) 300) LLIILRRRIARKQAHAHSK (SEQ ID NO: YGRRARRAARR (SEQ ID NO: 709) 301) LLIILRRRIRAQAHAHSK (SEQ ID NO: YGRRARRRARR (SEQ ID NO: 710) 302) LLIILRRRIRKAAHAHSK (SEQ ID NO: YGRRARRRRRR (SEQ ID NO: 711) 303) LLIILRRRIRKQaHAHSK YGRRRRRRRRR (SEQ ID NO: 712) LLIILRRRIRKQAAAHSK (SEQ ID NO: YRRRRRRRRRR (SEQ ID NO: 713) 304) LLIILRRRIRKQAHaHSK GKINLKALAALAKKIL (SEQ ID NO: 714) LLIILRRRIRKQAHAASK (SEQ ID NO: RVIRVWFQNKRCKDKK (SEQ ID NO: 715) 305) LLIILRRRIRKQAHAHAK (SEQ ID NO: GRKKRRQRRRPPQGRKKRRQRRRPPQGRKKRRQRRRPPQ 306) (SEQ ID NO: 716) LLIILRRRIRKQAHAHSA (SEQ ID NO: GEQIAQLIAGYIDIILKKKKSK (SEQ ID NO: 717) 307) KSHAHAQKRIRRRLIILL (SEQ ID NO: GRKKRRQRRRPPQC (SEQ ID NO: 718) 308) lliilrrrirkqahahsk AAVALLPAVLLALLAPRKKRRQRRRPPQ (SEQ ID NO: 719) RRIRPRP (SEQ ID NO: 309) AAVALLPAVLLALLAPRKKRRQRRRPPQC (SEQ ID NO: 720) RRIRPRPPRLPRPRP (SEQ ID NO: 310) AAVALLPAVLLALLAPRKKRRQRRRPPQ (SEQ ID NO: 721) RRIRPRPPRLPRPRPRPLPFPRPG (SEQ RKKRRQRRRPPQCAAVALLPAVLLALLAP (SEQ ID NO: ID NO: 311) 722) RRIRPRPPRLPRPRPRP (SEQ ID NO: 312) RRRQRRKRGGDIMGEWGNEIFGAIAGFLG (SEQ ID NO: 723) PRPPRLPRPRPRPLPFPRPG (SEQ ID NO: RRRQRRKRGGDIMGEWGNEIFGAIAGFLG (SEQ ID NO: 313) 723) PPRLPRPRPRPLPFPRPG (SEQ ID NO: YGRKKRRQRRRGCYGRKKRRQRRRG (SEQ ID NO: 724) 314) RLPRPRPRPLPFPRPG (SEQ ID NO: 315) GRKKRRQRRRPPQ (SEQ ID NO: 725) PRPRPRPLPFPRPG (SEQ ID NO: 316) AAVALLPAVLLALLAPRRRRRR (SEQ ID NO: 726) PRPRPLPFPRPG (SEQ ID NO: 317) RLWRALPRVLRRLLRP (SEQ ID NO: 727) PRPLPFPRPG (SEQ ID NO: 318) AAVALLPAVLLALLAPSGASGLDKRDYV (SEQ ID NO: 728) RKKRRQRRR (SEQ ID NO: 319) LLETLLKPFQCRICMRNFSTRQARRNHRRRHRR (SEQ ID NO: 729) RQGAARVTSWLGRQLRIAGKRLEGRSK AAVACRICMRNFSTRQARRNHRRRHRR (SEQ ID NO: 730) (SEQ ID NO: 320) RVTSWLGRQLRIAGKRLEGRSK (SEQ RQIKIWFQNRRMKWKK (SEQ ID NO: 731) ID NO: 321) GROLRIAGKRLEGRSK (SEQ ID NO: RQIKIWFQNRRMKWKK (SEQ ID NO: 731) 322) RRVTSWLGRQLRIAGKRLEGRSK (SEQ RQIKIWFQNRRMKWKKDIMGEWGNEIFGAIAGFLG (SEQ ID NO: 323) ID NO: 732) RVRSWLGRQLRIAGKRLEGRSK (SEQ SGRGKQGGKARAKAKTRSSRAGLQFPVGRVHRLLRKG ID NO: 324) (SEQ ID NO: 733) GRQLRIAGKRLRGRSK (SEQ ID NO: 325) SGRGKQGGKARAKAKTRSSRAGLQFPVGRVHRLLRKGC (SEQ ID NO: 734) GRQLRIAGRRLRGRSR (SEQ ID NO: 326) KKDGKKRKRSRKESYSVYVYKVLKQ (SEQ ID NO: 735) GRQLRRAGRRLRGRSR (SEQ ID NO: 327) KGSKKAVTKAQKKDGKKRKRSRKESYSVYVYKVLKQ (SEQ ID NO: 736) GRQLRIAGRRLRRRSR (SEQ ID NO: 328) GWTLNSAGYLLGKINLKALAALAKKIL (SEQ ID NO: 737) GRQLRRA GRRLRRRSR (SEQ ID NO: KLALKLALKALKAALKLA (SEQ ID NO: 738) 329) RQLRIAGRRLRGRSR (SEQ ID NO: 330) KETWWETWWTEWSQPKKKRKV (SEQ ID NO: 739) rsrgrlrrgairlqrg KETWWETWWTEWSQPGRKKRRQRRRPPQ (SEQ ID NO: 740) KLIKGRTPIKFGKADCDRPPKHSQNGM RVIRWFQNKRCKDKK (SEQ ID NO: 741) GK (SEQ ID NO: 331) KLIKGRTPIKFGKADCDRPPKHSQNGM LGLLLRHLRHHSNLLANI (SEQ ID NO: 742) (SEQ ID NO: 332) KLIKGRTPIKFGKADCDRPPKHSQNGK KLWSAWPSLWSSLWKP (SEQ ID NO: 743) (SEQ ID NO: 333) KGRTPIKFGKADCDRPPKHSQNGMGK GLGSLLKKAGKKLKQPKSKRKV (SEQ ID NO: 744) (SEQ ID NO: 334) KLIKGRTPIKFGKADCDRPPKHSGK FKQqQqQqQqQq (SEQ ID NO: 335) KLIKGRTPIKFGKARCRRPPKHSGK YRFK (SEQ ID NO: 745) (SEQ ID NO: 336) KLIKGRTPIKFGK (SEQ ID NO: 337) YRFKYRFKYRLFK (SEQ ID NO: 746) KRIPNKKPGKKTTTKPTKKPTIKTTKKD WRFKKSKRKV (SEQ ID NO: 747) LKPQTTKPK (SEQ ID NO: 338) KRIPNKKPGKKTTTKPTKKPTIKTTKKD WRFKAAVALLPAVLLALLAP (SEQ ID NO: 748) LK (SEQ ID NO: 339) KRIPNKKPGKKTTTKPTKKPTIKTTKK WRFKWRFK (SEQ ID NO: 749) (SEQ ID NO: 340) KRIPNKKPGKKTTTKPTKKPTIK (SEQ WRFKWRFKWRFK (SEQ ID NO: 750) ID NO: 341) KRIPNKKPGKKTTTKPTKK (SEQ ID NO: KGSKKAVTKAQKKDGKKRKRSRKESYSVYVYKVLKQ 342) (SEQ ID NO: 751) KRIPNKKPGKKT (SEQ ID NO: 343) RGSRRAVTRAQRRDGRRRRRSRRESYSVYVYRVLRQ (SEQ ID NO: 752) KRIPNKKPGKK (SEQ ID NO: 344) RVIRWFQNKRSKDKK (SEQ ID NO: 753) KRIPNKKPKK (SEQ ID NO: 345) GWTLNSAGYLLGKINLKALAALAKKIL (SEQ ID NO: 754) RRIPNRRPRR (SEQ ID NO: 346) AAVALLPAVLLALLAPRKKRRQRRRPPQ (SEQ ID NO: 755) KKPGKKTTTKPTKKPTIKTTKK (SEQ ID CWKKK (SEQ ID NO: 756) NO: 347) KKPGKKTTTKPTKK (SEQ ID NO: 348) CWKKKKKKKK (SEQ ID NO: 757) KKPTIKTTKK (SEQ ID NO: 349) CWKKKKKKKKKKKKK (SEQ ID NO: 758) KKTTTKPTKK (SEQ ID NO: 350) CWKKKKKKKKKKKKKKKKKK (SEQ ID NO: 759) KSICKTIPSNKPKKK (SEQ ID NO: 351) KKKKKKKKKKKKKKKKKKK (SEQ ID NO: 760) KTIPSNKPKKK (SEQ ID NO: 352) kkwkmrrGaGrrrrrrrrr KPRSKNPPKKPK (SEQ ID NO: 353) APWHLSSQYSRT (SEQ ID NO: 761) DRDDRDDRDDRDDRDDR (SEQ ID NO: AAVALLPAVLLALLAKKNNLKDCGLF (SEQ ID NO: 762) 354) ERERERERERERER (SEQ ID NO: 355) AAVALLPAVLLALLAKKNNLKECGLY (SEQ ID NO: 763) WRWRWRWRWRWRWR (SEQ ID NO: 356) AAVALLPAVLLALLAVTDQLGEDFFAVDLEAFLQEFGLLP EKE (SEQ ID NO: 764) DRDRDRDRDR (SEQ ID NO: 357) AAVALLPAVLLALLAK (SEQ ID NO: 765) GALFLGFLGAAGSTMGAWSQPKKKRKV AHALCLTERQIKIWFQNRRMKWKKEN (SEQ ID NO: 766) (SEQ ID NO: 358) DRRRRGSRPSGAERRRRRAAAA (SEQ AHALCPPERQIKIWFQNRRMKWKKEN (SEQ ID NO: 767) ID NO: 359) DRRRRGSRPSGAERRRR (SEQ ID NO: 360) AYALCLTERQIKIWFANRRMKWKKEN (SEQ ID NO: 768) QTRRRERRAEKQAQW (SEQ ID NO: 361) GGVCPKILKKCRRDSDCPGACICRGNGYCGSGSD (SEQ ID NO: 769) RRRERRAEK (SEQ ID NO: 362) GGVCPKILAACRRDSDCPGACICRGNGYCGSGSD (SEQ ID NO: 770) NRARRNRRRVR (SEQ ID NO: 363) GGVCPAILKKCRRDSDCPGACICRGNGYCGSGSD (SEQ ID NO: 771) RTRRNRRRVR (SEQ ID NO: 364) GGVCPKILAKCRRDSDCPGACICRGNGYCGSGSD (SEQ ID NO: 772) RNRSRHRR (SEQ ID NO: 365) GGVCPKILKACRRDSDCPGACICRGNGYCGSGSD (SEQ ID NO: 773) KCPSRRPKR (SEQ ID NO: 366) GLPVCGETCVGGTCNTPGCKCSWPVCTRN (SEQ ID NO: 774) KRPAAIKKAGQAKKKK (SEQ ID NO: 367) GLPVCGETCVGGTCNTPGCTCSWPKCTRN (SEQ ID NO: 775) TRRSKRRSHRKF (SEQ ID NO: 368) GRCTKSIPPICFPD (SEQ ID NO: 776) RAGLQFPVGR VHRLLRK (SEQ ID NO: RQIKIWFQNRRMKWKK (SEQ ID NO: 777) 369) MVRRFLVTLRIRRACGPPRVRV (SEQ RQIKIWFQNRRMKWKKTYADFIASGRTGRRNAI (SEQ ID ID NO: 370) NO: 778) FVTRGCPRRLVARLIRVMVPRR (SEQ GRKKRRQRRRPPQ (SEQ ID NO: 779) ID NO: 371) VRRFLVTLRIRRA (SEQ ID NO: 372) GRKKRRQRRRPPQTYADFIASGRTGRRNAI (SEQ ID NO: 780) RVRILARFLRTRV (SEQ ID NO: 373) AGYLLGKINLKALAALAKKIL (SEQ ID NO: 781) RVRVFVVHIPRLT (SEQ ID NO: 374) AGYLLGKINLKALAALAKKILTYADFIASGRTGRRNAI (SEQ ID NO: 782) VIRVHFRLPVRTV (SEQ ID NO: 375) RRRRRRRRRRR (SEQ ID NO: 51) MVRRFLVTLRIRRACGPPRVRVFVVHIP RRRRRRRRRRRTYADFIASGRTGRRNAI (SEQ ID NO: 783) RLTGEWAAP (SEQ ID NO: 376) FRVPLRIRPCVVAPRLVMVRHTFGRIAR RRRRRRRRR (SEQ ID NO: 50) WVAGPLETR (SEQ ID NO: 377) AGYLLGKINLKALAALAKKIL (SEQ ID RRRRRRRRR (SEQ ID NO: 50) NO: 378) GTKMIFVGIKKKEERADLIAYLKKA RRRRRRRRR (SEQ ID NO: 50) (SEQ ID NO: 379) KKKEERADLIAYLKKA (SEQ ID NO: 380) rrrrrrrrr KMIFVGIKKKEERA (SEQ ID NO: 381) rrrrrrrrr KMIFVGIKKK (SEQ ID NO: 382) rrrrrrrrr EKGKKIFIMK (SEQ ID NO: 383) rrrrrrrrrk KGKKIFIMK (SEQ ID NO: 384) rRRRRRRRr RRRRNRTRRNRRRVRGC (SEQ ID NO: 385) rRrRrRrRr TRRQRTRRARRNRGC (SEQ ID NO: 386) RQIKIWFQNRRMKWKK (SEQ ID NO: 784) KMTRAQRRAAARRNRWTARGC (SEQ RQIKIWFQNRRMKWKK (SEQ ID NO: 784) ID NO: 387) KLTRAQRRAAARKNKRNTRGC (SEQ rqikiwfqnrrmkwkk ID NO: 388) NAKTRRHERRRKLAIERGC (SEQ ID rqikiwfqnrrmkwkk NO: 389) MDAQTRRRERRAEKQAQWKAANGC KCFQWQRNMRKVRGPPVSCIKR (SEQ ID NO: 785) (SEQ ID NO: 390) TAKTRYKARRAELIAERRGC (SEQ ID KCFQWQRNMRKVRGPPVSCIKR (SEQ ID NO: 785) NO: 391) SQMTRQARRLYBGC (SEQ ID NO: 392) kcfqwqrnmrkvrgppvscikr KRRIRRERNKMAAAKSRNRRRELTDTG kcfqwqrnmrkvrgppvscikr C (SEQ ID NO: 393) RIKAERKRMRNRIAASKSRKRKLERIAR KLALKLALKALKAALKLAGC (SEQ ID NO: 786) GC (SEQ ID NO: 394) KRARNTEAARRSRARKLQRMKQGC KLULKLULKULKAULKLUGC (SEQ ID NO: 395) KCFQWQRNMRKVRGPPVSCIKR (SEQ GGGARKKAAKAARKKAAKAARKKAAKAARKKAAKA ID NO: 396) (SEQ ID NO: 787) KCFQWQRNMRKVRGPPVSC (SEQ ID GRKKRRQRRRPPQC (SEQ ID NO: 788) NO: 397) KCFQWQRNMRKVRGPPVSSIKR (SEQ TRQARRNRRRRWRERQRGC (SEQ ID NO: 789) ID NO: 398) KCFQWQRNMRKVR (SEQ ID NO: 399) RRRRNRTRRNRRRVRGC (SEQ ID NO: 790) FQWQRNMRKVRGPPVS (SEQ ID NO: 400) KMTRAQRRAAARRNRWTARGC (SEQ ID NO: 791) QWORNMRKVRGPPVSCIKR (SEQ ID TRRQRTRRARRNRGC (SEQ ID NO: 792) NO: 401) QWORNMRKVR (SEQ ID NO: 402) RIKAERKRMRNRIAASKSRKRKLERIARGC (SEQ ID NO: 793) RRRRRRRRR (SEQ ID NO: 50) KRRIRRERNKMAAAKSRNRRRELTDTGC (SEQ ID NO: 794) RQIKIWFQNRRMKWKK (SEQ ID NO: 403) WLRRIKAWLRRIKALNRQLGVAA (SEQ ID NO: 795) KCFMWQEMLNKAGVPKLRCARK (SEQ crkkrrqrrr ID NO: 404) KETWWETWWTEWSQPKKKRKV (SEQ crrrrrrrrr ID NO: 405) KETWFETWFTEWSQPKKKRKV (SEQ ckkkkkkkkk ID NO: 406) KWFETWFTEWPKKRK (SEQ ID NO: 407) GRKKRRQRRRPP (SEQ ID NO: 796) GLWRALWRLLRSLWRLLWRA (SEQ ID RRRRRRRRR (SEQ ID NO: 50) NO: 408) GLWWRLWWRLRSWFRLWFRA (SEQ RRRRRRRR (SEQ ID NO: 2) ID NO: 409) DAATATRGRSAASRPTQRPRAPARSAS rrrrrrrr RPRRPVE (SEQ ID NO: 410) GALFLGFLGAAGSTMGAWSQPKKKRKV AKVKDEPQRRSARLSAKPAPPKPEPKPKKAPAKK (SEQ ID (SEQ ID NO: 411) NO: 797) GALFLGFLGAAGSTMGAWSQPKSKRKV (SEQ ID NO: 412)

Table 5 shows the selection examples of the targeting peptide, including but not limited to the target proteins indicated by “target protein name” and the peptide sequences corresponding to the target proteins. There are about 19,813 target proteins in total, including all known target proteins and all targeting peptides targeting these target proteins. Due to their large size, the inventors only screened dozens of representative target proteins as examples. However, the claimed target proteins in the present invention are all target proteins and targeting peptides known in the art, and is not limited to these dozens of target proteins, as shown in Table 5 below.

Target protein name Peptide sequence A COVALENT ENZYME-SUBSTRATE AXXXX (SEQ ID NO: 798) INTERMEDIATE WITH SACCHARIDE DISTORTION IN A MUTANT T4 LYSOZYME C-SRC (SH2 DOMAIN) COMPLEXED XEX WITH ACE-MALONYL TYR-GLU-(N,N- DIPENTYL AMINE) MHC CLASS I MOLECULE B*5301 TPYDINQML (SEQ ID NO: 799) COMPLEXED WITH PEPTIDE TPYDINQML FROM GAG PROTEIN OF HIV2 MHC CLASS I MOLECULE B*3501 VPLRPMTY (SEQ ID NO: 800) COMPLEXED WITH PEPTIDE VPLRPMTY FROM THE NEF PROTEIN (75-82) OF HIV1 MHC CLASS I MOLECULE B*5301 KPIVQYDNF (SEQ ID NO: 801) COMPLEXED WITH PEPTIDE LS6 (KPIVQYDNF) FROM THE MALARIA PARASITE P. FALCIPARUM HCV NS3 PROTEASE DOMAIN:NS4A GSVVIVGRIVLSGKPA (SEQ ID NO: 802) PEPTIDE COMPLEX HCV NS3 PROTEASE DOMAIN:NS4A GSVVIVGRIVLSGKPA (SEQ ID NO: 802) PEPTIDE COMPLEX HCV NS3 PROTEASE DOMAIN:NS4A KGSVVIVGRIVLSGKPAIIPK (SEQ ID NO: 803) PEPTIDE COMPLEX HCV NS3 PROTEASE DOMAIN:NS4A KGSVVIVGRIVLSGKPAIIPK (SEQ ID NO: 803) PEPTIDE COMPLEX STRUCTURE OF THROMBIN INHIBITED TFGSGEADCGLRPLFEKKSLEDKTERELLESYIDGR BY AERUGINOSAN298-A FROM A BLUE- (SEQ ID NO: 804) GREEN ALGA STRUCTURE OF THROMBIN INHIBITED DFEEIPEEXL (SEQ ID NO: 805) BY AERUGINOSAN298-A FROM A BLUE- GREEN ALGA STRUCTURE OF THROMBIN INHIBITED XLXX (SEQ ID NO: 806) BY AERUGINOSAN298-A FROM A BLUE- GREEN ALGA COMPLEX OF TROPONIN C WITH A 47 EEKRNRAITARRQHLKSVMLQIAATELEKEE (SEQ RESIDUE (1-47) FRAGMENT OF ID NO: 807) TROPONIN I HIV-1 PROTEASE COMPLEXED WITH A EDL TRIPEPTIDE INHIBITOR HIV-1 PROTEASE COMPLEXED WITH A EDL TRIPEPTIDE INHIBITOR COMPLEX OF HUMAN ALPHA- ADCGLRPLFEKKSLEDKTERELLESYI (SEQ ID NO: THROMBIN WITH THE BIFUNCTIONAL 808) BORONATE INHIBITOR BOROLOG1 CRYSTAL STRUCTURE OF BOVINE TPGVY (SEQ ID NO: 809) GAMMA-CHYMOTRYPSIN CRYSTAL STRUCTURE OF BOVINE TPGVY (SEQ ID NO: 809) GAMMA-CHYMOTRYPSIN STRUCTURE OF THE HIRULOG 3- SGEADCGLRPLFEKKSLEDKTERELLESYIDGR (SEQ THROMBIN COMPLEX AND NATURE OF ID NO: 810) THE S' SUBSITES OF SUBSTRATES AND INHIBITORS STRUCTURE OF THE HIRULOG 3- XPXGGGGGNGDXEEIPEEYL (SEQ ID NO: 811) THROMBIN COMPLEX AND NATURE OF THE S' SUBSITES OF SUBSTRATES AND INHIBITORS STRUCTURE OF THE HIRULOG 3- ADCGLRPLFEKKSLEDKTERELLESYI (SEQ ID NO: THROMBIN COMPLEX AND NATURE OF 812) SUBSITES OF SUBSTRATES INHIBITORS NMR SOLUTION STRUCTURE OF AN KHWVYY (SEQ ID NO: 813) ALPHA-BUNGAROTOXIN(SLASH) NICOTINIC RECEPTOR PEPTIDE COMPLEX COMPLEX OF THROMBIN WITH AND EADCGLRPLFEKKSLEDKTERELLESYI (SEQ ID NO: INHIBITOR CONTAINING A NOVEL P1 814) MOIETY COMPLEX OF THROMBIN WITH AND DFEEIPEEXL (SEQ ID NO: 815) INHIBITOR CONTAINING A NOVEL P1 MOIETY HUMAN ALPHA-THROMBIN INHIBITION TFGSGEADCGLRPLFEKKSLEDKTERELLESYIDGR BY EOC-D-PHE-PRO-AZALYS-ONP (SEQ ID NO: 816) HUMAN ALPHA-THROMBIN INHIBITION DFEEIPEEXL (SEQ ID NO: 815) BY EOC-D-PHE-PRO-AZALYS-ONP HUMAN ALPHA-THROMBIN INHIBITION TFGSGEADCGLRPLFEKKSLEDKTERELLESYIDGR BY CBZ-PRO-AZALYS-ONP (SEQ ID NO: 817) HUMAN ALPHA-THROMBIN INHIBITION DFEEIPEEXL (SEQ ID NO: 815) BY CBZ-PRO-AZALYS-ONP CRYSTAL STRUCTURE OF BOVINE CGVPAIQPVL (SEQ ID NO: 818) GAMMA-CHYMOTRYPSIN COMPLEXED WITH A SYNTHETIC INHIBITOR CRYSTAL STRUCTURE OF BOVINE CGVPAIQPVL (SEQ ID NO: 818) GAMMA-CHYMOTRYPSIN COMPLEXED WITH A SYNTHETIC INHIBITOR ANTAGONIST HIV-1 GAG PEPTIDES GGRKKYKL (SEQ ID NO: 819) INDUCE STRUCTURAL CHANGES IN HLA B8-HIV-1 GAG PEPTIDE (GGRKKYKL-3R MUTATION) ANTAGONIST HIV-1 GAG PEPTIDES GGKKKYQL (SEQ ID NO: 820) INDUCE STRUCTURAL CHANGES IN HLA B8-HIV-1 GAG PEPTIDE (GGKKKYQL-7Q MUTATION) ANTAGONIST HIV-1 GAG PEPTIDES GGKKKYKL (SEQ ID NO: 821) INDUCE STRUCTURAL CHANGES IN HLA B8-HIV-1 GAG PEPTIDE (GGKKKYKL-INDEX PEPTIDE) ANTAGONIST HIV-1 GAG PEPTIDES GGKKKYRL (SEQ ID NO: 822) INDUCE STRUCTURAL CHANGES IN HLA B8-HIV-1 GAG PEPTIDE (GGKKKYRL-7R MUTATION) ANTAGONIST HIV-1 GAG PEPTIDES GGKKRYKL (SEQ ID NO: 823) INDUCE STRUCTURAL CHANGES IN HLA B8-HIV-1 GAG PEPTIDE (GGKKRYKL-5R MUTATION) CRYSTAL STRUCTURE OF HUMAN EADCGLRPLFEKKSLEDKTERELLESYI (SEQ ID NO: ALPHA-THROMBIN COMPLEXED WITH 824) HIRUGEN AND P- AMIDINOPHENYLPYRUVATE AT 1.6 ANGSTROMS RESOLUTION CRYSTAL STRUCTURE OF HUMAN DFEEIPEEXL (SEQ ID NO: 825) ALPHA-THROMBIN COMPLEXED WITH HIRUGEN AND P- AMIDINOPHENYLPYRUVATE AT 1.6 ANGSTROMS RESOLUTION HLA-DR1 (DRA, DRB1 0101) HUMAN SDWRFLRGYHQYA (SEQ ID NO: 826) CLASS II HISTOCOMPATIBILITY PROTEIN (EXTRACELLULAR DOMAIN) COMPLEXED WITH ENDOGENOUS PEPTIDE HLA-DR1 (DRA, DRB1 0101) HUMAN GSDWRFLRGYHQYA (SEQ ID NO: 827) CLASS II HISTOCOMPATIBILITY PROTEIN (EXTRACELLULAR DOMAIN) COMPLEXED WITH ENDOGENOUS PEPTIDE CLEAVED ANTICHYMOTRYPSIN A349R GTIVRFNRPFLMIIVPTDTQNIFFMSKVTNPKQ (SEQ ID NO: 828)

In Table 1-Table 5, “e3 ligand” in Table 3 represents all the currently applicable small molecule ligands of E3 ligase. There are two types of linkers, one is “PEG linkers” shown in Table 2, and the other linker is collected in “linkers” in Table 1. “CPP list” in Table 4 is all the currently applicable cell-penetrating peptides. “Target interacting peptide” in Table 5 is the currently applicable targeting peptide examples of all targets.

At present, due to technical limitations, only about 10-20% of the targets can be developed. However, for the CePPiTAC technology provided by the present invention, peptides are used instead of small molecules to target the target protein, and connected to the cell-penetrating peptide sequence to ensure the complex is able to enter the cell membrane. Since any target protein can be screened for binding to the resistant peptides that can be linked to it, in theory, any target protein can be targeted to be degraded by proteases. Therefore, the application market is extremely broad. The previous “non-targetable” target proteins may be degraded by the drugs developed by the technology. Moreover, since the interactions between many proteins and proteins have long been established, it is very convenient to screen ligand peptides. There are now a number of high-efficiency small molecule E3 ligase ligands, which are very simple to connect with peptides and will be very convenient to design drugs with time and effort saved and develop various new drugs quickly and economically according to the present invention.

Example 3

The inventors also combine the targeting peptide with two or multiple different E3 ligase conjugates as shown below to efficiently degrade target proteins, which is specifically as shown in FIG. 2 .

Example 4

The inventors also contemplate degrading multiple targets related to the formation of pathogenic protein-protein complexes to inhibit entire pathogenic pathways as well as degrading multiple targets to completely inhibit a specific disease. To achieve this, the inventors designed the peptide degrader as shown in FIG. 3 .

Example 5

A representative PROTAC peptide conjugate PEN-FFW-LINK-LEN is synthesized, wherein PEN, FFW and LEN represent cell-penetrating peptide, targeting peptide and small molecule ligand, respectively.

a. Solid-Phase Synthesis of Peptide 1:

Scheme 1:

As shown in FIG. 4 , peptide 1 was synthesized at 0.15 mmol.

The SYRO automated peptide synthesizer was used to assist in elongation of the full sequence. 0.5 g Fmoc-Ile Wang resin (0.3 mmol/g) was swollen in DMF, and the Fmoc-moiety was deprotected using 20% piperidine/DMF (2 times for 5 min and 20 min, respectively). After each deprotection, the resin was washed with DMF (3×10 mL). On the synthesizer, each fmoc-amino acid residue (4 eq, 0.6 mmol) was treated with two different activator, DIC/Oxyma (4 eq, 0.6 mmol, 30 min) and HATU/DIPEA (4 eq, 0.6 mmol, 45 min) in DMF, to double-couple resins. The final Fmoc-moiety was deprotected using 20% piperidine/DMF (2 times for 5 min and 20 min, respectively) and washed with DMF (3×10 mL) to provide resin-bound linear peptide 1. The desired mass was determined by microlysis.

b. Synthesis of Lenalidomide-Conjugated Succinic Anhydride:

Scheme 1:

As shown in FIG. 5 , lenalidomide 2 (200 mg, 0.77 mmol) was added to a round bottom flask containing a solution of succinic anhydride 3 (90 mg, 0.93 mmol) in toluene (8 mL) and equipped with a reflux condenser. The mixture was refluxed for 3 h, and the precipitate was separated by vacuum filtration. The filter cake was washed with ethyl acetate (20 mL×2) and dried under vacuum to obtain product 4: 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxyisoindol-4-yl)amino)-4-oxobutyric acid. Yield: 120 mg, 43.4%.

c. Solid-Phase Synthesis and Resin Cleavage of LEN-Conjugated Peptides:

Scheme 3:

1. Solid-Phase Synthesis:

As shown in FIG. 6 , lenalidomide-conjugated succinic anhydride (4) was activated with DIC/Oxyma (4 eq) in DMF, added to the pre-treated resin-bound amine (200 mg, 0.06 mmol), and shaken well or for 2 h. with The resin was filtered and washed with DMF (3×10 mL) and DCM (3×10 mL), finally washed with diethyl ether (2×10 mL) and dried under vacuum for resin cleavage.

2. Resin Cleavage:

The product was isolated from 10 ml of resin containing trifluoroacetic acid, triisopropylsilane, and water (95:2.5:2.5) to provide 120 mg of crude peptide, which was purified by reversed-phase high performance liquid chromatography (HPLC) to obtain 10 mg of diastereomeric mixture 5 with a maximum purity of 97.15% and a purity of 93.19% at 214 nm. Yield: 10 mg, 6.68%.

Table 6 shows the preparation conditions for HPLC.

Instrument Agilent Technologies 1260 infinity Column X-Select CSH C18 (250*19) mm 5 μm Mobile phase A 0.1% TFA aqueous solution Mobile phase B Acetonitrile Flow rate 15 mL/min Reaction time 22 mins Load capacity 10 mg/injection

Table 7 shows a gradient table.

Time % of mobile % of mobile (min) phase A phase B 0.0 90 10 15 50 50 15.1 0 100 19 0 100 19.1 90 10 22 90 10

Example 6

1. The target proteins of many diseases are membrane proteins, such as PD-1 and PD-L1. Although the inhibitor drugs against them are very commonly used, they have low efficacy and are prone to drug resistance. It is because target proteins PD-1 and PD-L1 are on the cell membrane, and it is difficult to develop small-molecule PD-1/PD-L1 degraders. However, the technology according to the present invention can target the intracellular parts of these two proteins and then degrade these two proteins.

2. Some disease targets are difficult to bind to small molecules due to their structure. Therefore, it is difficult to design for ordinary small molecules by PROTAC, such as the G12V variant of Kras protein. However, the technology according to the present invention can use peptides to bind to them and then degrade them.

3. Some virus-related proteins such as the novel coronavirus proteins or HIV virus-related proteins have few targets since conventional viral drugs focus on neutralizing antibodies or virus-inhibiting proteases to inhibit the virus, and once the virus mutates, the drugs developed will be useless. The CePPiTAC technology provided by the present invention can select viral structural proteins or proteases to be bound and targeted by peptides and then degrade them, so that the protein synthesis is damaged or the virus packaging fails. This will firstly expand the number of targets for viral drug research and development since many viral proteins that could not be targeted in the past can be targeted. Secondly, the structural protein that is not easily mutated can be bound to degrade the entire target protein, so the drug can be prepared without worries about any virus mutations.

Example 7

In order to illustrate the modulating targeting chimera molecule induced by a cell-penetrating peptide given in this application, the random combination of four “modules” in its basic structure and various selections, the inventors designed a modulating targeting chimera molecule for degrading novel coronavirus S protein HR2 (FIG. 7A), in which the cell-penetrating peptide module has a sequence of YGRKKRRQRRR (SEQ ID NO: 1), the targeting peptide module has a sequence of SAIGKIQDSLSSTAS (SEQ ID NO: 4), the Linker module is a small molecule composed of (PEG)4 with a structural formula of

and E3 small molecule ligand module is an E3 ligand targeting CRBN with a structural formula of

The degradation effect of the targeting chimera molecule with different dosages (nmol) on protein was verified by Western Blot (FIG. 7B). It can be seen that with the increase of dosage, the protein has been degraded (no expression).

In order to verify that the targeting chimera molecule provided in this application serves to degrade rather than inhibit, the inventor also designed and added the protease inhibitor MG132, which can inhibit the effect of the targeting chimera provided in this application. From the experimental results (FIG. 7C), it can be seen that the protein only added with the targeting chimera molecule still cannot be expressed, but the protein added with the targeting chimera molecule+MG132 can be expressed normally with an expression level comparable to that of the protein without adding the targeting chimera molecule. These results demonstrate that the role of the targeting chimera molecule is to degrade rather than inhibit the protein.

Studies have shown that the S protein on the surface of the coronavirus mediates the infection of target cells by the virus. It consists of two subunits, S1 and S2. The S1 subunit is responsible for binding to the receptor on the cell surface, and the S2 subunit functions to fuse the virus with the cell membrane. The S2 subunit contains important functional regions such as heptapeptide repeat domain 1 (HR1) and heptapeptide repeat domain 2 (HR2). During the fusion of the viral membrane, HR1 and HR2 fold to form a six-helix bundle structure (6HB) to bring the viral membrane and the cell membrane closer together for fusion reaction, so that the genetic material of the virus enters the target cell through the fusion hole. The targeting chimera molecule can bind to the HR2 subunit of the novel coronavirus S protein and degrade it, which inhibits the formation of the six-helix bundle structure, thereby interferes with the fusion of the virus and the cell membrane, prevents the virus from invading cells, and fundamentally achieves the purpose of preventing and treating the novel coronavirus disease.

Example 8

Similar to Example 7, in order to illustrate the “modulating” design of the present application, the inventors also designed modulating targeting chimera molecules for degrading novel coronavirus N protein, novel coronavirus M protein, novel coronavirus E protein, novel coronavirus Orf6 protein, Lag-3 protein, Her2 protein, SHP-2 protein, STAT5B protein, MUC16 protein, CTLA-4 protein, PCSK9 protein, PD-1 protein and PD-L1 protein, respectively (FIG. 8A-FIG. 20A).

In the modulating targeting chimera molecule for degrading novel coronavirus N protein, the cell-penetrating peptide module has a sequence of RRRRRRRR (SEQ ID NO: 2), the targeting peptide module has a sequence of PQEESEEEVEEP (SEQ ID NO: 5), the Linker module is a small molecule composed of (PEG)4 with a structural formula of

and E3 small molecule ligand module is an E3 ligand targeting VHL with a structural formula of

In the modulating targeting chimera molecule for degrading novel coronavirus M protein, the cell-penetrating peptide module has a sequence of YGRKKRRQRRR (SEQ ID NO: 1), the targeting peptide module has a sequence of PQEESEEEVEEP (SEQ ID NO: 5), the Linker module is a small molecule composed of (PEG)4 with a structural formula of

and E3 small molecule ligand module is an E3 ligand targeting IAP with a structural formula of

In the modulating targeting chimera molecule for degrading novel coronavirus E protein, the cell-penetrating peptide module has a sequence of YGRKKRRQRRR (SEQ ID NO: 1), the targeting peptide module has a sequence of GGKGLGKacGGA, the Linker module is a small molecule composed of (PEG)4 with a structural formula of

and E3 small molecule ligand module is an E3 ligand targeting CRBN with a structural formula of

In the modulating targeting chimera molecule for degrading novel coronavirus Orf6 protein, the cell-penetrating peptide module has a sequence of YGRKKRRQRRR (SEQ ID NO: 1), the targeting peptide module has a sequence of DTMVGWDKDARTK (SEQ ID NO: 7), the Linker module is a small molecule composed of (PEG)4 with a structural formula of

and E3 small molecule ligand module is an E3 ligand targeting VHL with a structural formula of

In the modulating targeting chimera molecule for degrading Lag-3 protein, the cell-penetrating peptide module has a sequence of YGRKKRRQRRR (SEQ ID NO: 1), the targeting peptide module has a sequence of FNGARSFIDI (SEQ ID NO: 8), the Linker module is a small molecule composed of (PEG)4 with a structural formula of

and E3 small molecule ligand module is an E3 ligand targeting CRBN with a structural formula of

In the modulating targeting chimera molecule for degrading Her2 protein, the cell-penetrating peptide module has a sequence of YGRKKRRQRRR (SEQ ID NO: 1), the targeting peptide module has a sequence of WARLWNYLYR (SEQ ID NO: 9), the Linker module is a small molecule composed of (PEG)4 with a structural formula of

and E3 small molecule ligand module is an E3 ligand targeting VHL with a structural formula of

In the modulating targeting chimera molecule for degrading SHP-2 protein, the cell-penetrating peptide module has a sequence of YGRKKRRQRRR (SEQ ID NO: 1), the targeting peptide module has a sequence of RSFIDIGSGT (SEQ ID NO: 10), the Linker module is a small molecule composed of (PEG)4 with a structural formula of

and E3 small molecule ligand module is an E3 ligand targeting CRBN with a structural formula of

In the modulating targeting chimera molecule for degrading STAT5B protein, the cell-penetrating peptide module has a sequence of YGRKKRRQRRR (SEQ ID NO: 1), the targeting peptide module has a sequence of KAVDG(p)YVKPQI (SEQ ID NO: 11), the Linker module is a small molecule composed of (PEG)4 with a structural formula of

and E3 small molecule ligand module is an E3 ligand targeting IAP with a structural formula of

In the modulating targeting chimera molecule for degrading MUC16 protein, the cell-penetrating peptide module has a sequence of YGRKKRRQRRR (SEQ ID NO: 1), the targeting peptide module has a sequence of WIDPVNGDTE (SEQ ID NO: 12), the Linker module is a small molecule composed of (PEG)4 with a structural formula of

and E3 small molecule ligand module is an E3 ligand targeting VHL with a structural formula of

In the modulating targeting chimera molecule for degrading CTLA-4 protein, the cell-penetrating peptide module has a sequence of YGRKKRRQRRR (SEQ ID NO: 1), the targeting peptide module has a sequence of ARHPSWYRPFEGCG (SEQ ID NO: 13), the Linker module is a small molecule composed of (PEG)4 with a structural formula of

and E3 small molecule ligand module is an E3 ligand targeting VHL with a structural formula of

In the modulating targeting chimera molecule for degrading PCSK9 protein, the cell-penetrating peptide module has a sequence of RQIKIWFQNRRMKWK (SEQ ID NO: 3), the targeting peptide module has a sequence of MESFPGWNLV(homoR)IGLLR (SEQ ID NO: 14), the Linker module is a small molecule composed of (PEG)4 with a structural formula of

and E3 small molecule ligand module is an E3 ligand targeting IAP with a structural formula of

In the modulating targeting chimera molecule for degrading PD-1 protein, the cell-penetrating peptide module has a sequence of YGRKKRRQRRR (SEQ ID NO: 1), the targeting peptide module has a sequence of FNWDYSLEELREKAKYK (SEQ ID NO: 15), the Linker module is a small molecule composed of (PEG)4 with a structural formula of

and E3 small molecule ligand module is an E3 ligand targeting CRBN with a structural formula of

In the modulating targeting chimera molecule for degrading PD-L1 protein, the cell-penetrating peptide module has a sequence of YGRKKRRQRRR (SEQ ID NO: 1), the targeting peptide module has a sequence of MPIFLDHILNKFWILHYA (SEQ ID NO: 16), the Linker module is a small molecule composed of (PEG)4 with a structural formula of

and E3 small molecule ligand module is an E3 ligand targeting CRBN with a structural formula of

Likewise, the degradation effect of the targeting chimera molecules with different dosages (nmol) on novel coronavirus N protein, novel coronavirus M protein, novel coronavirus E protein, novel coronavirus Orf6 protein, Lag-3 protein, Her2 protein, SHP-2 protein, STAT5B protein, MUC16 protein and CTLA-4 protein was verified by Western Blot (FIG. 8B-FIG. 17B). It can be seen that with the increase of dosage, the protein has been degraded (no expression).

Likewise, in order to verify that the targeting chimera molecule provided in this application serves to degrade rather than inhibit, the inventor also designed and added the protease inhibitor MG132, which can inhibit the effect of the targeting chimera provided in this application. From the experimental results (FIG. 8C-FIG. 16C and FIGS. 18B-20B), it can be seen that the protein only added with the targeting chimera molecule still cannot be expressed, but the protein added with the targeting chimera molecule+MG132 can be expressed normally with an expression level comparable to that of the protein without adding the targeting chimera molecule. These results demonstrate that the role of the targeting chimera molecule is to degrade rather than inhibit the protein.

The novel coronavirus N protein, which is abundant in coronaviruses, is a highly immunogenic protein involved in genome replication and regulation of cell signaling pathways. Degrading this protein with the targeting chimera molecule of this application can effectively inhibit the novel coronavirus and treat the disease caused by it.

The novel coronavirus M protein, as a membrane glycoprotein (M), is an integral part of the viral particle envelope. M protein is involved in the assembly and release of the next generation of viral particles, and plays an important role in the structural stability and functional expression of other structural proteins (S, E, N proteins). Degrading this protein with the targeting chimera molecule can effectively destroy the stability of the viral structure and inhibit viral function.

The novel coronavirus E protein (E, Envelope Protein) is an integral part of the viral particle envelope and is a small envelope glycoprotein. The main function of the E protein is to protect the RNA gene strand inside the virus. Degrading this protein with the targeting chimera molecule can reduce or even remove the protective mechanism of viral RNA, making the RNA strand more prone to breakage, thereby effectively inhibiting viral function.

The novel coronavirus Orf6 protein is the most toxic to human cells among the novel coronavirus proteins. Existing research has found that it can kill about half of human cells after being introduced into human cells and can effectively inhibit the innate immunity of host cells. Degrading this protein with the targeting chimera molecule can greatly reduce the toxicity of the novel coronavirus to the human immune system.

Lag-3 protein, lymphocyte activation gene 3, also known as CD233, is a type I transmembrane protein, which belongs to the immunoglobulin (Ig) superfamily and mainly expressed on the surface of activated T cells and NK cells. LAG-3 is a very promising immunotherapy target. Degrading this protein with the targeting chimera molecule can effectively block the inhibitory signal in the interaction between tumor cells and TIL in the tumor microenvironment, restore the immune surveillance function of TIL on tumor cells, and achieve antitumor effects.

Her2 protein, a transmembrane protein with tyrosine protein kinase activity, is a member of the EGFR family. HER2 gene amplification is one of the most important factors affecting the growth and metastasis of breast cancer. Degrading this protein with the targeting chimera molecule can promote the apoptosis of and inhibit the proliferation of breast tumors.

SHP-2 protein, encoded by protein tyrosine phosphatase nonreceptor 11 (PTPN11), is a well-validated PTP oncoprotein in humans and is emerging as an important target for the treatment of cancer. Hyperactivation of SHP2 plays a crucial pathogenic role. Degrading this protein with the targeting chimera molecule can effectively block or inhibit the activation of the SHP2 pathway, thereby significantly improving tumor treatment.

STAT5B protein is signal transducer and activator of transcription-5b. STAT signal is a regulatory signal of various tumors. Degrading this protein with the targeting chimera molecule can effectively cause the dysregulation of STAT signal, thereby inhibiting the proliferation and clone formation of tumor cells (such as osteosarcoma cells) and inducing cell arrest and apoptosis at G0/G1 phase.

MUC16 protein, the largest transmembrane mucin, is a well-established serum biomarker for ovarian cancer since MUC16 is known to be overexpressed on the surface of ovarian cancer cells and split/shed into the blood. It is believed to play an anti-apoptotic role in cancer cells. The ectopic expression of its C-terminal domain induces resistance to cisplatin in ovarian cancer cells, and this effect is mediated by the inhibition of p53. Degrading this protein with the targeting chimera molecule can effectively regulate the apoptosis of and inhibit the proliferation of cancer cells.

CTLA-4 protein, cytotoxic T lymphocyte-associated protein 4, also known as CD152 (cluster of differentiation 152), is a protein receptor that functions as an immune checkpoint and downregulates immune responses. Mutations in the CTLA-4 gene are not only associated with cancer, but also with type 1 diabetes, Graves' disease, Hashimoto's thyroiditis, celiac disease, systemic lupus erythematosus, thyroid-related orbitopathy, primary biliary cirrhosis and other autoimmune diseases. Degrading this protein with the targeting chimera molecule can effectively increase the immune activity of the body.

Example 9

In particular, in order to illustrate that the “modulating” design given in this application can also precisely target proteins with mutated amino acids, the inventors designed a modulating targeting chimera molecule for degrading KRAS protein with G12V mutation (FIG. 21A), in which the cell-penetrating peptide module has a sequence of RRRRRRRR (SEQ ID NO: 2), the targeting peptide module has a sequence of LYDVAGSDKY (SEQ ID NO: 17), the Linker module is a small molecule composed of (PEG)4 with a structural formula of

and E3 small molecule ligand module is an E3 ligand targeting IAP with a structural formula of

Likewise, the degradation effect of the targeting chimera molecule with different dosages (nmol) on KRAS protein with G12V mutation was verified by Western Blot and the expression level was recorded (FIG. 21B). It can be seen that with the increase of dosage, the protein has been degraded (the expression level gradually decreased).

In order to verify the precise targeting of the targeting chimera molecule, the inventors also verified the degradation effect of the targeting chimera molecule with different dosages (nmol) on non-mutated KRAS protein (wild type) by Western Blot and recorded the expression level (FIG. 21C). It can be seen that with the increase of dosage, the protein changes are not obvious (the expression level was slightly reduced, but not obvious), which fully shows that the targeting chimera molecule of this design can accurately target the KRAS protein with G12V mutation without basically degrading wild-type KRAS protein, indicating an extremely high accuracy of targeting and degradation.

KRAS (Kirsten Rat Sarcoma Viral Oncogene Homolog) is a GDP/GTP binding protein. KRAS is in an activated state when binding to GTP, and in an off state when binding to GDP. KRAS can be temporarily activated by growth factors or tyrosine kinases (such as EGFR). The activated KRAS can activate downstream such as the PI3K-AKT-mTOR signaling pathway that controls cell production, and the RAS-RAF-MEK-ERK signaling pathway that controls cell proliferation. The mutant KRAS will continue to activate even without the activation of kinases such as EGFR, leading to continuous proliferation of cells and eventually cancer. KRAS mutants are found in a variety of tumors, the most common including lung cancer, pancreatic cancer, etc. The targeting chimera molecule can accurately degrade the KRAS protein with G12V mutation, but has no effect on the wild-type KRAS protein, which greatly improves the targeted treatment efficiency of the mutant protein.

Example 10

In particular, in order to illustrate that the “modulating” design given in this application can also connect the dual-E3 ligand structure and increase the degradation efficiency of the protein, the inventors designed a modulating dual-E3 ligand targeting chimera molecule for degrading PCSK9 (FIG. 22A), in which the cell-penetrating peptide module has a sequence of RQIKIWFQNRRMKWK (SEQ ID NO: 3), the targeting peptide module has a sequence of MESFPGWNLV(homoR)IGLLR (SEQ ID NO: 14) and is connected to two different E3 small molecule ligand modules via two Linker modules, respectively, two different E3 small molecule ligand modules being the E3 ligands targeting CRBN and TAP, respectively, and the Linker modules and the E3 small molecule ligand modules have an overall structural formula of

Likewise, in order to verify that the targeting chimera molecule provided in this application serves to degrade rather than inhibit, the inventor also designed and added the protease inhibitor MG132, which can inhibit the effect of the targeting chimera provided in this application. From the experimental results (FIG. 22B), it can be seen that the protein only added with the targeting chimera molecule still cannot be expressed, but the protein added with the targeting chimera molecule+MG132 can be expressed normally with an expression level comparable to that of the protein without adding the targeting chimera molecule. These results demonstrate that the role of the targeting chimera molecule is to degrade rather than inhibit the protein.

In addition, compared with FIG. 18A and FIG. 18B (the targeting chimera molecule for degrading PCSK9 protein also), the targeting chimera molecule with dual-E3 ligands has a lower dosage (from 25 nmol to 15 nmol) under the same degradation effect. Besides, since this targeting chimera molecule has dual-E3 ligands, after one of the linked E3 ubiquitinases mutates and develops drug resistance, the other E3 ubiquitinase can continue to function, increasing the reliability of the targeting chimera molecule.

Example 11

In particular, in order to illustrate that the “modulating” design given in this application can also target different protein targets and degrade two or even multiple proteins simultaneously, the inventors designed a dual-target modulating targeting chimera molecule for degrading the novel coronavirus HR2 protein and the novel coronavirus N protein simultaneously (FIG. 23A), in which the cell-penetrating peptide module has a sequence of YGRKKRRQRRR (SEQ ID NO: 1), the targeting peptide modules have sequences of SAIGKIQDSLSSTAS (SEQ ID NO: 4) and PQEESEEEVEEP (SEQ ID NO: 5) respectively, the Linker module is a small molecule composed of (PEG)4 with a structural formula of

and E3 small molecule ligand module is an E3 ligand targeting CRBN with a structural formula of

Likewise, in order to verify that the dual-target targeting chimera molecule provided in this application serves to degrade rather than inhibit, the inventor also designed and added the protease inhibitor MG132, which can inhibit the effect of the targeting chimera provided in this application. From the experimental results (FIG. 23B), it can be seen that the protein only added with the targeting chimera molecule still cannot be expressed, but the protein added with the targeting chimera molecule+MG132 can be expressed normally with an expression level comparable to that of the protein without adding the targeting chimera molecule. These results demonstrate that the role of the targeting chimera molecule is to degrade rather than inhibit the protein.

In addition, the use of this dual-target targeting chimera molecule can degrade HR2 protein and N protein simultaneously. Based on this consideration, the inventors can also design targeting chimera molecules targeting three targets, four targets or even more targets, which can degrade a variety of proteins simultaneously to achieve better applicability and wider use conditions. Considering the space limitation of the application, it will not be repeated here, but the technical protection of multi-target targeting chimera molecule should not be limited by the dual-target targeting chimera molecule described in this example.

Example 12

In particular, in order to illustrate that the “modulating” design given in this application can also modify the targeting peptide module to achieve the purpose of eliminating cell-penetrating peptide connection or increasing structural stability, the inventors designed a modulating targeting chimera molecule with stapled peptide modification and cyclic peptide modification (FIG. 24A and FIG. 25A).

Likewise, the degradation effect of the targeting chimera molecule with different dosages (nmol) on PD-L1 protein was verified by Western Blot (FIG. 24B and FIG. 25B). It can be seen that with the increase of dosage, the protein has been degraded (the expression level gradually decreased).

The principle of the stapled peptide modification and the cyclic peptide modification is to make the targeting peptide module assume a state similar to the secondary structure of the protein, forming a “mini-protein”, which can still avoid the decomposition of the peptide during cell-penetrating in the case of not connecting the cell-penetrating peptide module, effectively increasing the stability of the targeting peptide module.

The modification process of the stapled peptide (targeting peptide module) includes: modifying and linking CGIQDTNSKKQSDTHLEETC (SEQ ID NO: 831) to two compounds R8 and S5 (the structures are as follows), so that the peptide becomes:

  CGIQDT(R8)NSKKQS(S5)DTHLEET-.

R8 is Fmoc-R8-OH, and the structural formula is as follows:

S5 is Fmoc-S5-0H, and the structural formula is as follows:

Stapled peptide (or mini-protein)+E3 small molecule ligand chimeric structure:

The targeting chimera molecule containing stapled peptide has a structural formula of:

The overall structure is shown in FIGS. 30-32 . FIGS. 30-32 show a structural representation of a stapled peptide+small molecule ligand chimera. Among them, terminal A in FIG. 30 is connected to terminal A in FIG. 31 , and terminal B in FIG. 31 is connected to terminal B in FIG. 32 . The combination of FIGS. 30-32 shows the structure of a chimera molecule compound containing a stapled peptide.

Cyclic Peptide+Small Molecule E3 Ligand Chimera Structure:

The structural formula of cyclic peptide (targeting peptide module): Linker-3PEG, Binder (ligand): CRBN (full name Cereblon):

Linker module is a small molecule composed of (PEG)4 with a structural formula of

E3 small molecule ligand module is an E3 ligand targeting CRBN with a structural formula of

Cyclization method: The two cysteine disulfide bonds in the above figure form a ring.

The overall structure is shown in FIGS. 33-35 . FIGS. 33-35 show another structural representation of a cyclic peptide+small molecule ligand chimera. Among them, terminal Ain FIG. 33 is connected to terminal A in FIG. 34 , terminal B in FIG. 33 is connected to terminal B in FIG. 34 , and terminal D in FIG. 34 is connected to terminal D in FIG. 35 . The combination of FIGS. 33-35 shows the structure of a chimera molecule compound containing a cyclic peptide.

Example 13

The applicant has retrieved three prior art documents related to the technology in the present invention, and compared the technology with the technical solution of the present invention for the technical effect.

Document 1:

Specific Knockdown of a-Synuclein by Peptide-Directed Proteasome Degradation Rescued ItsAssociated Neurotoxicity (Jing Qu, Xiaoxi Ren, Fenqin Xue, Haixia Huang, Wei Wang, Jianliang Zhang, Cell Chemical Biology, 2020).

Document 2:

Specific Knockdown of Endogenous Tau Protein by Peptide-Directed Ubiquitin-ProteasomeDegradation (Ting-Ting Chu, Na Gao, Qian-Qian Li, . . . , Yong-Xiang Chen, Yu-Fen Zhao, Yan-Mei Li, Cell Chemical Biology, 2016).

Document 3:

A PROTAC peptide induces durable β-catenin degradation and suppresses Wnt-dependentintestinal cancer (Hongwei Liao 1, Xiang Li 2, Lianzheng Zhao 1, Yalong Wang 1, Xiaodan Wang 1, Ye Wu 2, Xin Zhou 3, Wei Fu 3, Lei Liu 4, Hong-Gang Hu 2,5 and Ye-Guang Chen 1, Cell Discovery, 2020).

Document 1 and Document 2 disclose the composition of cell-penetrating peptide+targeting peptide+peptide Linker+peptide Binder, in which Document 1 does not a significant degradation effect on target protein until 50 μm (FIG. 3 ), and Document 2 does not a significant effect on the target protein until 100 μm (FIG. 2 ).

Document 3 discloses the composition of stapled peptide+peptide Linker+polypeptide Binder, and Document 3 does not have a significant degradation effect on the target until 70 μm (FIG. 1 ).

The targeting chimera molecule provided by the technical solution of the present invention can degrade the target protein at the nm level, and the specific comparison is shown in Table 8.

TABLE 8 Dosage of the drug when the target protein is degraded Example 7 (novel coronavirus S protein HR2, FIGS. 7A-C) 50-100 nmol Example 8 (novel coronavirus N protein, FIGS. 8A-C) 50-100 nmol Example 8 (novel coronavirus M protein, FIGS. 9A-C) 50-100 nmol Example 8 (novel coronavirus E protein, FIGS. 10A-C) 10-100 nmol Example 8 (novel coronavirus Orf6 protein, FIGS. 11A-C) 50-100 nmol Example 8 (Lag-3 protein, FIGS. 12A-C) 75-100 nmol Example 8 (Her2 protein, FIGS. 13A-C) 10-100 nmol Example 8 (SHP-2 protein, FIGS. 14A-C) 10-100 nmol Example 8 (STAT5B protein, FIGS. 15A-C) 75-100 nmol Example 8 (MUC16 protein, FIGS. 16A-C) 50-100 nmol Example 8 (CTLA-4 protein, FIGS. 17A-B) 10-75 nmol Example 8 (PCSK9 protein, FIGS. 18A-B) 25 nmol Example 8 (PD-1 protein, FIGS. 19A-B) 25 nmol Example 8 (PD-L1 protein, FIGS. 20A-B) 30 nmol Example 9 (KRAS protein G12V mutation, FIGS. 21A-C) 30 nmol Example 10 (dual-E3, PCSK9 protein, FIGS. 22A-C) 15 nmol Example 11 (dual-target, novel coronavirus HR2 protein + 15 nmol novel coronavirus N protein, FIGS. 23A-C) Example 12 (stapled peptide-modified, PD-L1 protein, 50-75 nmol FIGS. 24A-C) Example 12 (cyclic peptide-modified, PD-L1 protein, 30 nmol FIGS. 25A-C) Document 1 50 μmol Document 2 100 μmol Document 3 70 μmol

It can be seen from Table 8 that the targeting chimera molecule provided in this application can degrade the target protein in the order of nmol (the highest is 100 nmol, i.e., 0.1 μmol), while in Documents 1-3, the minimum level of 50 μmol is required to produce significant degradation effect on the target protein. The difference between the two is at least 500 times in the dosage of the degrader, with a very obvious difference in effect.

Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, but not to limit them. Although the present invention has been described in detail in conjunction with the foregoing embodiments, those of ordinary skill in the art should understand that the technical solutions described in the foregoing embodiments can still be modified, or some or all of the technical features thereof can be equivalently replaced; and these modifications or replacements will not make the spirit of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention. 

1. A modulating targeting chimera molecule induced by a cell-penetrating peptide, comprising at least one cell-penetrating peptide module, at least one targeting peptide module and at least one small molecule ligand module connected with each other, wherein the targeting peptide module is a peptide sequence that can bind to a targeted protein.
 2. The modulating targeting chimera molecule induced by the cell-penetrating peptide according to claim 1, further comprising at least one Linker module, wherein the targeting peptide module is chimeric with the small molecule ligand module through the Linker module.
 3. The modulating targeting chimera molecule induced by the cell-penetrating peptide according to claim 2, wherein the cell-penetrating peptide module is connected to the free end of the targeting peptide module and used to guide the targeting chimera molecule for penetrating the cell membrane.
 4. The modulating targeting chimera molecule induced by the cell-penetrating peptide according to claim 3, wherein the small molecule ligand module is a small molecule E3 ligand that can bind to E3 ligase, preferably, the protease degrader adapted to the small molecule E3 ligand is one or more of CRBN (Cereblon protein), VHL (von Hippel-Lindau) and IAP (Inhibitor of apoptosis proteins).
 5. The modulating targeting chimera molecule induced by the cell-penetrating peptide according to claim 1, wherein the cell-penetrating peptide module has an amino acid sequence of any one of SEQ ID No.1-SEQ ID No.3.
 6. The modulating targeting chimera molecule induced by the cell-penetrating peptide according to claim 1, wherein the targeting peptide module has an amino acid sequence of any one or more of SEQ ID No.4-SEQ ID No.17.
 7. The modulating targeting chimera molecule induced by the cell-penetrating peptide according to claim 1, wherein the Linker module is a small molecule compound with a structural formula shown in formula I:


8. The modulating targeting chimera molecule induced by the cell-penetrating peptide according to claim 1, wherein: when the adapted protease degrader is CRBN, the structural formula of the small molecule ligand module is shown in formula II:

when the adapted protease degrader is VHL, the structural formula of the small molecule ligand module is shown in formula III:

and when the adapted protease degrader is TAP, the structural formula of the small molecule ligand module is as shown in formula IV:


9. The modulating targeting chimera molecule induced by the cell-penetrating peptide according to claim 5, having a structure of any one or more of the following structures: 1) the cell-penetrating peptide of SEQ ID No.1+the targeting peptide of SEQ ID No.4+the Linker of formula I+the small molecule ligand of formula II; 2) the cell-penetrating peptide of SEQ ID No.2+the targeting peptide of SEQ ID No.5+the Linker of formula I+the small molecule ligand of formula III; 3) the cell-penetrating peptide of SEQ ID No.1+the targeting peptide of SEQ ID No.5+the Linker of formula I+the small molecule ligand of formula IV; 4) the cell-penetrating peptide of SEQ ID No.1+the targeting peptide of SEQ ID No.6+the Linker of formula I+the small molecule ligand of formula II; 5) the cell-penetrating peptide of SEQ ID No.1+the targeting peptide of SEQ ID No.7+the Linker of formula I+the small molecule ligand of formula III; 6) the cell-penetrating peptide of SEQ ID No.1+the targeting peptide of SEQ ID No.8+the Linker of formula I+the small molecule ligand of formula II; 7) the cell-penetrating peptide of SEQ ID No.1+the targeting peptide of SEQ ID No.9+the Linker of formula I+the small molecule ligand of formula III; 8) the cell-penetrating peptide of SEQ ID No.1+the targeting peptide of SEQ ID No.10+the Linker of formula I+the small molecule ligand of formula II; 9) the cell-penetrating peptide of SEQ ID No.1+the targeting peptide of SEQ ID No.11+the Linker of formula I+the small molecule ligand of formula IV; 10) the cell-penetrating peptide of SEQ ID No.1+the targeting peptide of SEQ ID No.12+the Linker of formula I+the small molecule ligand of formula III; 11) the cell-penetrating peptide of SEQ ID No.1+the targeting peptide of SEQ ID No.13+the Linker of formula I+the small molecule ligand of formula III; 12) the cell-penetrating peptide of SEQ ID No.3+the targeting peptide of SEQ ID No.14+the Linker of formula I+the small molecule ligand of formula IV; 13) the cell-penetrating peptide of SEQ ID No.1+the targeting peptide of SEQ ID No.15+the Linker of formula I+the small molecule ligand of formula II; 14) the cell-penetrating peptide of SEQ ID No.1+the targeting peptide of SEQ ID No.16+the Linker of formula I+the small molecule ligand of formula II; 15) the cell-penetrating peptide of SEQ ID No.2+the targeting peptide of SEQ ID No.17+the Linker of formula I+the small molecule ligand of formula IV; 16) the cell-penetrating peptide of SEQ ID No.3+the targeting peptide of SEQ ID No.14+the Linker of formula I+(dual E3 ligands: the small molecule ligand of formula II+the small molecule ligand of formula III); and 17) the cell-penetrating peptide of SEQ ID No.1+(dual targets: the targeting peptide of SEQ ID No.4+the targeting peptide of SEQ ID No.5)+the Linker of formula I+the small molecule ligand of formula II.
 10. The modulating targeting chimera molecule induced by the cell-penetrating peptide according to claim 5, wherein the targeting peptide module further comprises a modified stapled peptide sequence or circular peptide sequence, and the stapled peptide sequence or circular peptide sequence has a function of cell penetration.
 11. The modulating targeting chimera molecule induced by the cell-penetrating peptide according to claim 10, wherein the stapled peptide has a structural formula shown in formula V:

and the cyclic peptide has a structural formula shown in formula VI:


12. The modulating targeting chimera molecule induced by the cell-penetrating peptide according to claim 11, wherein the modulating targeting chimera molecule induced by the cell-penetrating peptide containing the stapled peptide has the structure as follows: the stapled peptide of formula V+the Linker of formula I+the small molecule ligand of formula II.
 13. The modulating targeting chimera molecule induced by the cell-penetrating peptide according to claim 11, wherein the modulating targeting chimera molecule induced by the cell-penetrating peptide containing the circular peptide has the structure as follows: the circular peptide of formula VI+the Linker of formula I+the small molecule ligand of formula II.
 14. A method of preparing a product for degrading a targeted protein or a product for degrading a targeted protein with a mutant amino acid position with the modulating targeting chimera molecule induced by the cell-penetrating peptide of claim
 1. 15. The method according to claim 14, wherein the degraded targeted protein comprises one or more of the novel coronavirus S protein HR2, novel coronavirus N protein, novel coronavirus M protein, novel coronavirus E protein, novel coronavirus Orf6 protein, LAG-3 protein, Her2 protein, SHP-2 protein, STAT5B protein, MUC16 protein, CTLA-4 protein, PCSK9 protein, PD-1 protein, PD-L1 protein and KRAS protein with G12V mutation. 